REFERENCE TO RELATED APPLICATIONS
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] This invention provides compounds having drug and bio-affecting properties, their
pharmaceutical compositions and method of use. In particular, the invention is concerned
with azaindole piperazine diamide derivatives that possess unique antiviral activity.
More particularly, the present invention relates to compounds useful for the treatment
of HIV and AIDS.
Background Art
[0003] HIV-1 (human immunodeficiency virus -1) infection remains a major medical problem,
with an estimated 33.6 million people infected worldwide. The number of cases of HIV
and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 1999, 5.6 million
new infections were reported, and 2.6 million people died from AIDS. Currently available
drugs for the treatment of HIV include six nucleoside reverse transcriptase (RT) inhibitors
(zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir), three non-nucleoside
reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz), and six
peptidomimetic protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir,
amprenavir and lopinavir). Each of these drugs can only transiently restrain viral
replication if used alone. However, when used in combination, these drugs have a profound
effect on viremia and disease progression. In fact, significant reductions in death
rates among AIDS patients have been recently documented as a consequence of the widespread
application of combination therapy. However, despite these impressive results, 30
to 50% of patients ultimately fail combination drug therapies. Insufficient drug potency,
non-compliance, restricted tissue penetration and drug-specific limitations within
certain cell types (e.g. most nucleoside analogs cannot be phosphorylated in resting
cells) may account for the incomplete suppression of sensitive viruses. Furthermore,
the high replication rate and rapid turnover of HIV-1 combined with the frequent incorporation
of mutations, leads to the appearance of drug-resistant variants and treatment failures
when sub-optimal drug concentrations are present (Larder and Kemp; Gulick; Kuritzkes;
Morris-Jones
et al; Schinazi
et al; Vacca and Condra; Flexner; Berkhout and Ren
et al; (Ref. 6-14)). Therefore, novel anti-HIV agents exhibiting distinct resistance patterns,
and favorable pharmacokinetic as well as safety profiles are needed to provide more
treatment options.
[0004] Currently marketed HIV-1 drugs are dominated by either nucleoside reverse transcriptase
inhibitors or peptidomimetic protease inhibitors. Non-nucleoside reverse transcriptase
inhibitors (NNRTIs) have recently gained an increasingly important role in the therapy
of HIV infections (Pedersen & Pedersen, Ref 15). At least 30 different classes of
NNRTI have been described in the literature (De Clercq, Ref. 16) and several NNRTIs
have been evaluated in clinical trials. Dipyridodiazepinone (nevirapine), benzoxazinone
(efavirenz) and bis(heteroaryl) piperazine derivatives (delavirdine) have been approved
for clinical use. However, the major drawback to the development and application of
NNRTIs is the propensity for rapid emergence of drug resistant strains, both in tissue
cell culture and in treated individuals, particularly those subject to monotherapy.
As a consequence, there is considerable interest in the identification of NNRTIs less
prone to the development of resistance (Pedersen & Pedersen, Ref 15).
[0005] Several indole derivatives including indole-3-sulfones, piperazino indoles, pyrazino
indoles, and 5H-indolo[3,2-b][1,5]benzothiazepine derivatives have been reported as
HIV-1 reverse transciptase inhibitors (Greenlee et al, Ref. 1; Williams et al, Ref.
2; Romero et al, Ref. 3; Font et al, Ref. 17; Romero et al, Ref. 18; Young et al,
Ref. 19; Genin et al, Ref. 20; Silvestri et al, Ref. 21). Indole 2-carboxamides have
also been described as inhibitors of cell adhesion and HIV infection (Boschelli et
al,
US 5,424,329, Ref. 4). Finally, 3-substituted indole natural products (Semicochliodinol A and
B, didemethylasterriquinone and isocochliodinol) were disclosed as inhibitors of HIV-1
protease (Fredenhagen et al, Ref. 22). Other indole derivatives exhibiting antiviral
activity useful for treating HIV are disclosed in PCT
WO 00/76521 (Ref. 93). Also, indole derivatives are disclosed in
PCT WO 00/71535 (Ref. 94).
[0006] Structurally related aza-indole amide derivatives have been disclosed previously
(Kato et al, Ref. 23; Levacher et al, Ref. 24; Dompe Spa,
WO-09504742, Ref. 5(a); SmithKline Beecham PLC,
WO-09611929, Ref. 5(b); Schering Corp.,
US-05023265, Ref. 5(c)). However, these structures differ from those claimed herein in that they
are aza-indole mono-amide rather than unsymmetrical aza-indole piperazine diamide
derivatives, and there is no mention of the use of these compounds for treating viral
infections, particularly HIV. Other azaindoles have been also disclosed by Wang et
al, Ref. 95. Nothing in these references can be construed to disclose or suggest the
novel compounds of this invention and their use to inhibit HIV infection.
REFERENCES CITED
Patent documents
[0007]
- 1. Greenlee, W.J.; Srinivasan, P.C. Indole reverse transcriptase inhibitors. U.S. Patent 5,124,327.
- 2. Williams, T.M.; Ciccarone, T.M.; Saari, W. S.; Wai, J.S.; Greenlee, W.J.; Balani,
S.K.; Goldman, M.E.; Theohrides, A.D. Indoles as inhibitors of HIV reverse transcriptase.
European Patent 530907.
- 3. Romero, D.L.; Thomas, R.C.; Preparation of substituted indoles as anti-AIDS pharmaceuticals.
PCT WO 93 /01181.
- 4. Boschelli, D.H.; Connor, D.T.; Unangst, P.C. Indole-2-carboxamides as inhibitors
of cell adhesion. U.S. Patent 5,424,329.
- 5. (a) Mantovanini, M.; Melillo, G.; Daffonchio, L. Tropyl 7-azaindol-3-ylcarboxyamides
as antitussive agents. PCT WO 95/04742 (Dompe Spa). (b) Cassidy, F.; Hughes, I.; Rahman, S.; Hunter, D. J. Bisheteroaryl-carbonyl
and carboxamide derivatives with 5HT 2C/2B antagonists activity. PCT WO 96/11929. (c) Scherlock, M. H.; Tom, W. C. Substituted 1H-pyrrolopyridine-3-carboxamides. U. S. Patent 5,023,265.
Other Publications
[0008]
6. Larder, B.A.; Kemp, S.D. Multiple mutations in the HIV-1 reverse transcriptase confer
high-level resistance to zidovudine (AZT). Science, 1989, 246,1155-1158.
7. Gulick, R.M. Current antiretroviral therapy: An overview. Quality of Life Research,
1997, 6, 471-474.
8. Kuritzkes, D.R. HIV resistance to current therapies. Antiviral Therapy, 1997, 2 (Supplement
3), 61-67.
9. Morris-Jones, S.; Moyle, G.; Easterbrook, P.J. Antiretroviral therapies in HIV-1 infection.
Expert Opinion on Investigational Drugs, 1997, 6(8),1049-1061.
10. Schinazi, R.F.; Larder, B.A.; Mellors, J.W. Mutations in retroviral genes associated
with drug resistance. International Antiviral News, 1997, 5,129-142,.
11. Vacca, J.P.; Condra, J.H. Clinically effective HIV-1 protease inhibitors. Drug Discovery
Today, 1997, 2, 261-272.
12. Flexner, D. HIV-protease inhibitors. Drug Therapy, 1998, 338, 1281-1292.
13. Berkhout, B. HIV-1 evolution under pressure of protease inhibitors: Climbing the stairs
of viral fitness. J. Biomed. Sci., 1999, 6, 298-305.
14. Ren, S.; Lien, E. J. Development of HIV protease inhibitors: A survey. Prog. Drug
Res., 1998, 51, 1-31.
15. Pedersen, O.S.; Pedersen, E.B. Non-nucleoside reverse transcriptase inhibitors: the
NNRTI boom. Antiviral Chem. Chemother. 1999,10, 285-314.
16. (a) De Clercq, E. The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs)
in the therapy of HIV-1 infection. Antiviral Research, 1998, 38, 153-179. (b) De Clercq, E. Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs)
in the therapy of HIV infection. IL. Farmaco, 1999, 54, 26-45.
17. Font, M.; Monge, A.; Cuartero, A.; Elorriaga, A.; Martinez-Irujo, J.J.; Alberdi, E.;
Santiago, E.; Prieto, I.; Lasarte, J.J.; Sarobe, P. and Borras, F. Indoles and pyrazino[4,5-b]indoles
as nonnucleoside analog inhibitors of HIV-1 reverse transcriptase. Eur. J. Med. Chem.,
1995, 30, 963-971.
18. Romero, D.L.; Morge, R.A.; Genin, M.J.; Biles, C.; Busso, M,; Resnick, L.; Althaus,
I.W.; Reusser, F.; Thomas, R.C and Tarpley, W.G. Bis(heteroaryl)piperazine (BHAP)
reverse transcriptase inhibitors: structure-activity relationships of novel substituted
indole analogues and the identification of 1-[(5-methanesulfonamido-1H-indol-2-yl)-carbonyl]-4-[3-[1-methylethyl)amino]-pyridinyl]piperazine
momomethansulfonate (U-90152S), a second generation clinical candidate. J. Med. Chem.,
1993, 36, 1505-1508.
19. Young, S.D.; Amblard, M.C.; Britcher, S.F.; Grey, V.E.; Tran, L.O.; Lumma, W.C.; Huff,
J.R.; Schleif, W.A.; Emini, E.E.; O'Brien, J.A.; Pettibone, D.J. 2-Heterocyclic indole-3-sulfones
as inhibitors of HIV-reverse transcriptase. Bioorg. Med. Chem. Lett., 1995, 5, 491-496.
20. Genin, M.J.; Poel, T.J.; Yagi, Y.; Biles, C.; Althaus, I.; Keiser, B.J.; Kopta, L.A.;
Friis, J.M.; Reusser, F.; Adams, W.J.; Olmsted, R.A.; Voorman, R.L.; Thomas, RC. and
Romero, D.L. Synthesis and bioactivity of novel bis(heteroaryl)piperazine (BHAP) reverse
transcriptase inhibitors: structure-activity relationships and increased metabolic
stability of novel substituted pyridine analogs. J. Med Chem., 1996, 39, 5267-5275.
21. Silvestri, R.; Artico, M.; Bruno, B.; Massa, S.; Novellino, E.; Greco, G.; Marongiu,
M.E.; Pani, A.; De Montis, A and La Colla, P. Synthesis and biological evaluation
of 5H-indolo[3,2-b][1,5]benzothiazepine derivatives, designed as conformationally
constrained analogues of the human immunodeficiency virus type 1 reverse transcriptase
inhibitor L-737,126. Antiviral Chem. Chemother. 1998, 9, 139-148.
22. Fredenhagen, A.; Petersen, F.; Tintelnot-Blomley, M.; Rosel, J.; Mett, H and Hug,
P. J. Semicochliodinol A and B: Inhibitors of HIV-1 protease and EGF-R protein Tyrosine
Kinase related to Asterriquinones produced by the fungus Chrysosporium nerdarium.
Antibiotics, 1997, 50, 395-401.
23. Kato, M.; Ito, K.; Nishino, S.; Yamakuni, H.; Takasugi, H. New 5-HT3 (Serotonin-3)
receptor antagonists. IV. Synthesis and structure-activity relationships of azabicycloalkaneacetamide
derivatives. Chem. Pharm. Bull., 1995, 43, 1351-1357.
24. Levacher, V.; Benoit, R.; Duflos, J; Dupas, G.; Bourguignon, J.; Queguiner, G. Broadening
the scope of NADH models by using chiral and non chiral pyrrolo [2,3-b] pyridine derivatives.
Tetrahedron, 1991, 47, 429-440.
25. Shadrina, L.P.; Dormidontov, Yu.P.; Ponomarev, V,G.; Lapkin, I.I. Reactions of organomagnesium
derivatives of 7-aza- and benzoindoles with diethyl oxalate and the reactivity of
ethoxalylindoles. Khim. Geterotsikl. Soedin., 1987, 1206-1209.
26. Sycheva, T.V.; Rubtsov, N.M.; Sheinker, Yu.N.; Yakhontov, L.N. Some reactions of 5-cyano-6-chloro-7-azaindoles
and lactam-lactim tautomerism in 5-cyano-6-hydroxy-7-azaindolines. Khim. Geterotsikl.
Soedin., 1987, 100-106.
27. (a) Desai, M.; Watthey, J.W.H.; Zuckerman, M. A convenient preparation of 1-aroylpiperazines.
Org. Prep. Proced Int., 1976, 8, 85-86. (b) Adamczyk, M.; Fino, J.R. Synthesis of procainamide metabolites. N-acetyl desethylprocainamide
and desethylprocainamide. Org. Prep. Proced Int. 1996, 28, 470-474. (c) Rossen, K.; Weissman, S.A.; Sager, J.; Reamer, R.A.; Askin, D.; Volante, R.P.; Reider,
P.J. Asymmetric Hydrogenation of tetrahydropyrazines: Synthesis of (S)-piperazine
2-tert-butylcarboxamide, an intermediate in the preparation of the HIV protease inhibitor
Indinavir. Tetrahedron Lett., 1995, 36, 6419-6422. (d) Wang, T.; Zhang, Z.; Meanwell, N.A. Benzoylation of Dianions: Preparation of mono-Benzoylated
Symmetric Secondary Diamines. J. Org. Chem., 1999, 64,7661-7662.
28. Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M. 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one
(DEPBT): A new coupling reagent with remarkable resistance to racemization. Organic
Lett., 1999, 1, 91-93.
29. Harada, N.; Kawaguchi, T.; Inoue, I.; Ohashi, M.; Oda, K.; Hashiyama, T.; Tsujihara,
K. Synthesis and antitumor activity of quaternary salts of 2-(2'-oxoalkoxy)-9-hydroxyellipticines.
Chem. Pharm. Bull., 1997, 45, 134-137.
30. Schneller, S. W.; Luo, J.-K. Synthesis of 4-amino-1H-pyrrolo[2,3-b]pyridine (1,7-Dideazaadenine)
and 1H-pyrrolo[2,3-b]pyridin-4-ol (1,7-Dideazahypoxanthine). J. Org. Chem., 1980,
45, 4045-4048.
31. Shiotani, S.; Tanigochi, K. Furopyridines. XXII [1]. Elaboration of the C-substitutents
alpha to the heteronitrogen atom of furo[2,3-b]-, -[3.2-b]-, -[2.3-c]- and -[3,2-c]pyridine.
J. Het. Chem., 1997, 34, 901-907.
32. Minakata, S.; Komatsu, M.; Ohshiro, Y. Regioselective functionalization of 1H-pyrrolo[2,3-b]pyridine
via its N-oxide. Synthesis, 1992, 661-663.
33. Klemm, L. H.; Hartling, R. Chemistry of thienopyridines. XXIV. Two transformations
of thieno[2,3-b]pyridine 7-oxide (1). J Het. Chem., 1976, 13, 1197-1200.
34. Antonini, I.; Claudi, F.; Cristalli, G.; Franchetti, P.; Crifantini, M.; Martelli,
S. Synthesis of 4-amino-1-□-D-ribofuranosyl-1H-pyrrolo[2,3-b]pyridine (1-Deazatubercidin)
as a potential antitumor agent. J. Med. Chem., 1982, 25, 1258-1261.
35. (a) Regnouf De Vains, J.B.; Papet, A.L.; Marsura, A. New symmetric and unsymmetric polyfunctionalized
2,2'-bipyridines. J. Het. Chem., 1994, 31, 1069-1077. (b) Miura, Y.; Yoshida, M.; Hamana, M. Synthesis of 2,3-fused quinolines from 3-substituted
quinoline 1-oxides. Part II, Heterocycles, 1993, 36, 1005-1016. (c) Profft, V.E.; Rolle, W. Uber 4-merkaptoverbindungendes 2-methylpyridins. J. Prakt.
Chem., 1960, 283 (11), 22-34.
36. Nesi, R.; Giomi, D.; Turchi, S.; Tedeschi, P., Ponticelli, F. A new one step synthetic
approach to the isoxazolo[4,5-b]pyridine system. Synth. Comm., 1992, 22, 2349-2355.
37. (a) Walser, A.; Zenchoff, G.; Fryer, R.I. Quinazolines and 1,4-benzodiazepines. 75. 7-Hydroxyaminobenzodiazepines
and derivatives. J. Med. Chem., 1976, 19, 1378-1381. (b) Barker, G.; Ellis, G.P. Benzopyrone. Part I. 6-Amino- and 6-hydroxy-2-subtituted chromones.
J. Chem. Soc., 1970, 2230-2233.
38. Ayyangar, N.R; Lahoti, R J.; Daniel, T. An alternate synthesis of 3,4-diaminobenzophenone
and mebendazole. Org. Prep. Proced Int.,1991, 23, 627-631.
39. Mahadevan, I.; Rasmussen, M. Ambident heterocyclic reactivity: The alkylation of pyrrolopyridines
(azaindoles, diazaindenes). Tetrahedron, 1993, 49, 7337-7352.
40. Chen, B.K.; Saksela, K.; Andino, R.; Baltimore, D. Distinct modes of human immunodeficiency
type 1 proviral latency revealed by superinfection of nonproductively infected cell
lines with recombinant luciferase-encoding viruses. J. Virol., 1994, 68, 654-660.
41. Bodanszky, M.; Bodanszky, A. "The Practice of Peptide Synthesis" 2nd Ed., Springer-Verlag:
Berlin Heidelberg, Germany, 1994.
42. Albericio, F. et al. J. Org. Chem. 1998, 63, 9678.
43. Knorr, R. et al. Tetrahedron Lett. 1989, 30, 1927.
44. (a) Jaszay Z. M. et al. Synth. Commun., 1998 28, 2761 and references cited therein; (b) Bernasconi, S. et al. Synthesis, 1980, 385.
45. (a) Jaszay Z. M. et al. Synthesis, 1989, 745 and references cited therein; (b) Nicolaou, K. C. et al. Angew. Chem. Int. Ed 1999, 38, 1669.
46. Ooi, T. et al. Synlett. 1999, 729.
47. Ford, R. E. et al. J. Med. Chem. 1986, 29, 538.
48. (a) Yeung, K.-S. et al. Bristol-Myers Squibb Unpublished Results. (b) Wang, W. et al. Tetrahedron Lett. 1999, 40, 2501.
49. Brook, M. A. et al. Synthesis, 1983, 201.
50. Yamazaki, N. et al. Tetrahedron Lett. 1972, 5047.
51. Barry A. Bunin "The Combinatorial Index" 1998 Academic Press, San Diego / London pages
78-82.
52. Richard C. Larock Comprehensive Organic Transormations 2nd Ed. 1999, John Wiley and
Sons New York.
53. M.D. Mullican et.al. J.Med. Chem. 1991, 34, 2186-2194.
54. Protective groups in organic synthesis 3rd ed. / Theodora W. Greene and Peter G.M.
Wuts. New York : Wiley, 1999.
55. Katritzky, Alan R. Lagowski, Jeanne M. The principles of heterocyclic ChemistryNew
York : Academic Press, 1968
56. Paquette, Leo A. Principles of modern heterocyclic chemistry New York : Benjamin.
57. Katritzky, Alan R.; Rees, Charles W.; Comprehensive heterocyclic chemistry : the structure,
reactions, synthesis, and uses of heterocyclic compounds 1 st ed.Oxford (Oxfordshire)
; New York : Pergamon Press, 1984. 8 v.
58. Katritzky, Alan RHandbook of heterocyclic 1st edOxford (Oxfordshire) ; New York :
Pergamon Press, 1985.
59. Davies, David I Aromatic Heterocyclic Oxford; New York : Oxford University Press,
1991.
60. Ellis, G. P. Synthesis of fused Chichester [Sussex] ; New York : Wiley, c1987-c1992.
Chemistry of heterocyclic compounds ; v. 47.
61. Joule, J. A Mills, K. ,Smith, G. F. Heterocyclic Chemistry , 3rd ed London ;New York
Chapman & Hall, 1995.
62. Katritzky, Alan R., Rees, Charles W. , Scriven, Eric F. V. Comprehensive heterocyclic
chemistry II : a review of the literature 1982-1995.
63. The structure, reactions, synthesis, and uses of heterocyclic compounds 1 st ed. Oxford
; New York : Pergamon, 1996. 11 v. in 12 : ill. ; 28 cm.
64. Eicher, Theophil, Hauptmann, Siegfried. The chemistry of heterocycles : structure,
reactions, syntheses, and applications Stuttgart; New York: G. Thieme, 1995.
65. Grimmett, M. R. Imidazole and benzimidazole Synthesis London; San Diego : Academic
Press, 1997.
66. Advances in heterocyclic chemistry. Published in New York by Academic Press, starting
in 1963- present.
67. Gilchrist, T. L. (Thomas Lonsdale) Heterocyclic chemistry 3rd ed. Harlow, Essex :
Longman, 1997. 414 p. : ill. ; 24 cm.
68. Farina, Vittorio; Roth, Gregory P. Recent advances in the Stille reaction; Adv. Met.-Org.
Chem. 1996, 5, 1-53.
69. Farina, Vittorio; Krishnamurthy, Venkat; Scott, William J. The Stille reaction ; Org.
React. (N. Y.) (1997), 50, 1-652.
70. Stille, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508-524.
71. Norio Miyaura and Akiro Suzuki Chem Rev. 1995, 95, 2457.
72. Home, D.A. Heterocycles 1994, 39, 139.
73. Kamitori, Y. et.al. Heterocycles, 1994, 37(1), 153.
74. Shawali, J. Heterocyclic Chem. 1976, 13, 989.
75. a) Kende, A.S.et al. Org. Photochem. Synth. 1972, 1, 92. b) Hankes, L.V.; Biochem. Prep. 1966, 11, 63. c) Synth. Meth. 22, 837.
76. Hulton et. al. Synth. Comm. 1979, 9, 789.
77. Pattanayak, B.K. et.al. Indian J. Chem. 1978, 16, 1030.
78. Chemische Berichte 1902, 35, 1545.
79. Chemische Berichte Ibid 1911, 44, 493.
80. Moubarak, I., Vessiere, R. Synthesis 1980, Vol. 1, 52-53.
81. Ind J. Chem. 1973, 11, 1260.
82. Roomi et.al. Can J. Chem. 1970, 48, 1689.
83. Sorrel, T.N. J. Org. Chem. 1994, 59, 1589.
84. Nitz, T.J. et. al. J. Org. Chem. 1994, 59, 5828-5832.
85. Bowden, K. et.al. J. Chem. Soc. 1946, 953.
86. Nitz, T.J. et. al. J. Org. Chem. 1994, 59, 5828-5832.
87. Scholkopf et. al. Angew. Int. Ed Engl. 1971, 10(5), 333.
88. (a) Behun, J. D.; Levine, R. J. Org. Chem. 1961, 26, 3379. (b) Rossen, K.; Weissman, S.A.; Sager, J.; Reamer, R.A.; Askin, D.; Volante, R.P.; Reider,
P.J. Asymmetric Hydrogenation of tetrahydropyrazines: Synthesis of (S)-piperazine
2-tert-butylcarboxamide, an intermediate in the preparation of the HIV protease inhibitor
Indinavir. Tetrahedron Lett., 1995, 36, 6419-6422. (c) Jenneskens, L. W.; Mahy, J.; den Berg, E. M. M. de B.-v.; Van der Hoef, I.; Lugtenburg,
J. Recl. Trav. Chim. Pays-Bas 1995, 114, 97.
89. Wang, T.; Zhang, Z.; Meanwell, N.A. Benzoylation of Dianions: Preparation of mono-Benzoylated
Symmetric Secondary Diamines. J. Org. Chem., 1999, 64, 7661-7662.
90. (a) Adamczyk, M.; Fino, J.R. Synthesis of procainamide metabolites. N-acetyl desethylprocainamide
and desethylprocainamide. Org. Prep. Proced Int. 1996, 28, 470-474. (b) Wang, T.; Zhang, Z.; Meanwell, N.A. Regioselective mono-Benzoylation of Unsymmetrical
Piperazines. J. Org. Chem., in press.
91. Masuzawa, K.; Kitagawa, M.; Uchida, H. Bull Chem. Soc. Jpn. 1967, 40, 244-245.
92. Furber, M.; Cooper, M. E.; Donald, D. K. Tetrahedron Lett. 1993, 34, 1351-1354.
93. Blair, W. S. et al, PCT WO 00/76521 published December 21, 2000.
94. Mavunkel, B. J. et al, PCT WO 00/71535 published November 30,2000.
95. Wang, T. et al, PCT WO 01/62255 published August 30, 2001. 96. Wallace et al., PCT WO 02/04440 published January 17, 2002.
SUMMARY DESCRIPTION OF THE INVENTION
[0009] The present invention comprises compounds of Formula I, or pharmaceutically acceptable
salts thereof, which are effective antiviral agents, particularly as inhibitors of
HIV.
[0010] The invention relates to compounds of Formula I, including pharmaceutically acceptable
salts thereof,

wherein:
Q is either

and then R2 is selected from the group consisting of hydrogen, halogen and methoxy; and
R3 is hydrogen;
or Q is:

and R2 is halogen or hydrogen and R3 is hydrogen;
R4 is B;
B is selected from the group consisting of substituted phenyl, heteroaryl, and C(O)R7 wherein said heteroaryl is optionally substituted and phenyl is substituted with
one to three same or different halogens or from one to two same or different substituents
selected from the group F;
F is selected from the group consisting of (C1-6)alkyl, (C3-6)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6)alkoxy, (C1-6)thioalkoxy, cyano, halogen, carbonyl, benzyl, - NR42C(O)-(C1-6)alkyl, -NR42C(O)-(C3-6)cycloalkyl, -NR42C(O)-aryl, -NR42C(O)-heteroaryl, - NR42C(O)-heteroalicyclic, a cyclic N-amido, -NR42S(O)2-(C1-6)alkyl, -NR42S(O)2-(C3-6)cycloalkyl, -NR42S(O)2-aryl, -NR2S(O)2-heteroaryl, -NR42S(O)2-heteroalicyclic, -S(O)2 NR42R43, NR42R43, (C1-6)alkylC(O)NR42R43, C(O)NR42R43, NHC(O)NR42R43, OC(O)NR42R43, NHC(O)OR54', (C1-6)alkylNR42R43, COOR54, and (C1-6)alkylCOOR54 wherein said (C1-6)alkyl, (C3-6)cycloalkyl, aryl, heteroaryl, heteroalicyclic, (C1-6)alkoxy, are optionally substituted with one to three same or different halogens or
from one to two same or different substituents selected from the group G;
G is selected from the group consisting of (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, hcteroalicyclic, hydroxy, (C1-6)alkoxy, (C1-6)thioalkoxy, thioaryloxy, cyano, halogen, nitro, carbonyl, thiocarbonyl, benzyl, -NR48C(O)-(C1-6)alkyl, -NR48C(O)-(C3-6)cycloalkyl, - NR48C(O)-aryl, -NR48C(O)-heteroaryl, -NR48C(O)-heteroalicyclic, a cyclic N-amido, - NR48S(O)2-(C1-6)alkyl, - -NR48S(O)2-(C3-6)cycloalkyl, -NR48S(O)2-aryl, -NR48S(O)2-heteroaryl, -NR48S(O)2-heteroalicyclic, sulfonyl, -S(O)2 NR48R49, NR48R49, (C1-6)alkyl C(O)NR48R49, C(O)NR48R49, NHC(O)NR48R49, OC(O)NR48R49, NHC(O)OR54', (C1-6)alkylNR48R49, COOR54, and (C1-6)alkylCOOR54';
R1 is hydrogen;
m is 2;
R5 is hydrogen;
R6 does not exist;
R7 is selected from the group consisting of aryl, heteroaryl, and heteroalicyclic wherein
said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to
three same or different halogens or with from one to two same or different substituents
selected from the group F;
A is selected from the group consisting of phenyl and heteroaryl; wherein heteroaryl
is pyridinyl, furanyl or thienyl; and said phenyl or said heteroaryl is optionally
substituted with one to two of the same or different amino, C1-6alkyl, hydroxy, or halogen;
-W- is

R9, R10, R11, R12, R13, and R14 are each hydrogen; and
R15 and R16 are each independently hydrogen or methyl with the proviso that only one is methyl;
R42 and R43 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R42 and R43 taken together with the nitrogen to which they are attached form a heteroaryl ring
or a heteroalicyclic ring which may contain up to 2 additional heteroatoms selected
from N, O, S(O)m, wherein m' is 0, 1, or 2; and wherein said (C1-6)alkyl, (C1-ó)alkoxy, (C3-7cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with
one to three same or different halogens or from one to two same or different substituents
selected from the group G;
R48 and R49 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, allyl, aryl, heteroaryl, heteroalicyclic or R48 and R49 taken together with the nitrogen to which they are attached form a heteroaryl ring
or a heteroalicyclic ring which may contain up to two additional heteroatoms selected
from N, O, S(O)m, wherein m' is 0, 1, or 2;
R54 is selected from the group consisting of hydrogen, (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, and heteroalicyclic wherein said (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with
one to three same or different halogens or from one to two same or different substituents
selected from the group consisting of: amino, OH, and NR55R56;
R54' is selected from the group consisting of (C1-6)alkyl, (C3-7)cycloalky), aryl, heteroaryl, and heteroalicyclic wherein said (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with
one to three same or different halogens or from one to two same or different substituents
selected from the group consisting of: amino, OH, and NR55R56;
R55 and R56 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, or (C3-7)cycloalkyl.
[0011] A group of preferred compounds of Formula I, including pharmaceutically acceptable
salts thereof,
Q is

R4 is B;
A is Phenyl or 2-pyridyl;
B is heteroaryl, wherein said heteroaryl is optionally substituted with one to three
same or different halogens or from one to two same or different substituents selected
from the group F;
Most preferred among this group of preferred compounds are those where R4 is B;
A is Phenyl or 2-pyridyl and B is heteroaryl, wherein said heteroaryl is optionally
substituted with one to three same or different halogens or from one to two same or
different substituents selected from the group F;
Compounds where B is heteroaryl, wherein said heteroaryl is optionally substituted
with one to three same or different halogens or from one to two same or different
substituents selected from the group F claimed;
Preferred groups for B when B is heteroaryl are selected from the group consisting
of thiazole, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, furyl,
thienyl, oxazole, oxadiazole, thiadiazole, pyrimidine, pyrazole, triazine, triazole,
tetrazole, pyridyl, wherein said heteroaryl is optionally substituted with one to
three same or different halogens or from one to two same or different substituents
selected from the group F;
When B is heteroaryl, most preferred is when said heteroaryl is optionally substituted
with one to three same or different halogens or a substituent selected from the group
(C1-C6 alkyl), amino, -NHC(O)-(C1-C6 alkyl), -NHS(O)2-(C1-C6 alkyl), Methoxy,-C(O)-NH2, C(O)NHMe, C(O)NMe2, trifluoromethyl, -NHC (C1-C6 alkyl), -N(C1-C6 alkyl)2, -heteroaryl, cyclic N-amido; among the most prefered B is thienyl and when B is
thienyl most preferred is when the thienyl is optionally substituted with one to three
same or different halogens or a substituent selected from the group (C1-C6 alkyl), amino, -NHC(O)-(C1-C6 alkyl), -NHS(O)2-(C1-C6 alkyl), methoxy, -C(O)-NH2, C(O)NHMe, C(O)NMe2, trifluoromethyl, -NHC(C1-C6 alkyl), -N(C1-C6 alkyl)2, -heteroaryl, cyclic N-amido;
and even more preferred is when the thienyl is optionally substituted with one to
three same or different halogens or a substituent selected from the group (C1-C6 alkyl), amino, -NHC(O)-(C1-C6 alkyl), -NHS(O)2-(C1-C6 alkyl), methoxy, -C(O)-NH2, C(O)NHMe, C(O)NMe2, trifluoromethyl, -NHC(C1-C6 alkyl), -N(C1-C6 alkyl)2, -heteroaryl, cyclic N-amido;
A further group of preferred compounds of Formula I are, including pharmaceutically
acceptable salts thereof wherein,
Q is

R2 is selected from the group consisting of hydrogen, halogen, and methoxy;
R4 is B;
B is heteroaryl, wherein said heteroaryl is optionally substituted with one to three
same or different halogens or from one to two same or different substituents selected
from the group F;
Most preferred are compounds where A is Phenyl or 2-pyridyl;
Most preferred for B is as described above.
Preferred groups for B when B is heteroaryl are selected from the group consisting
of thiazole, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, furyl,
thienyl, oxazole, oxadiazole, thiadiazole, pyrimidine, pyrazole, triazine, triazole,
tetrazole, pyridyl, wherein said heteroaryl is optionally substituted with one to
three same or different halogens or from one to two same or different substituents
selected from the group F;
When B is heteroaryl, most preferred is when said heteroaryl is optionally substituted
with one to three same or different halogens or a substituent selected from the group
(C1-C6 alkyl), amino, -NHC(O)-(C1-C6 alkyl), -NHS(O)2-(C1-C6 alkyl), methoxy,-C(O)-NH2, C(O)NHMe, C(O)NMe2, trifluoromethyl, -NHC (C1-C6 alkyl), -N(C1-C6 alkyl)2, -heteroaryl, cyclic N-amido;
among the most preferred B is thienyl, pyrazole, or a six membered heteroaryl containing
two ring nitrogens.
and when B is one of these most preferred groups it is optionally substituted with
one to three same or different halogens or a substituent selected from the group (C1-C6 alkyl), amino, -NHC(O)-(C1-C6 alkyl), -NHS(O)2-(C1-C6 alkyl), methoxy, -C(O)-NH2, C(O)NHMe, C(O)NMe2, trifluoromethyl, -NHC(C1-C6 alkyl), -N (C1-C6 alkyl)2, -heteroaryl, cyclic N-amido;
and even more preferred is when said heteroaryl is optionally substituted with one
to three same or different halogens or a substituent selected from the group (C1-C6 alkyl), amino, NHC(O)-(C1-C6 alkyl), -NHS(O)2-(C1-C6 alkyl), methoxy, -C(O)-NH2, C(O)NHMe, C(O)NMe2, trifluoromethyl, NHC(C1-C6 alkyl), -N (C1-C6 alkyl)2, -heteroaryl, cyclic N-amido;
Another embodiment of a preferred aspect of the invention are compounds of Formula
I, including pharmaceutically acceptable salts thereof,
A is selected from the group consisting ofphenyl and heteroaryl in which said heteroaryl
is selected from pyridinyl, furanyl and thienyl, and said phenyl or said heteroaryl
is optionally substituted with one to two of the same or different amino, C1-6alkyl, or halogen;
R9, R10, R11, R12, R13, and R14 are each hydrogen; and
R15 and R16 are each independently hydrogen or methyl with the proviso that only one is methyl.
Q is either

and then R2 is selected from the group consisting of hydrogen, halogen and methoxy;
And R3 is hydrogen;
Or Q is:

and R2 is halogen or hydrogen and R3 is hydrogen;
R4 is B; and
F is selected from the group consisting of (C1-6)alkyl, hydroxy, heteroaryl, heteroalicyclic, methoxy, methylthioalkoxy, halogen,
carbonyl, C(O)NR42R43, -NR42C(O)-(C1-6)alkyl, -NR42C(O)-(C3-6)cycloalkyl, -NR4C(O)-aryl, -NR42C(O)-heteroaryl, -NR42C(O)-heteroalicyclic, a cyclic N-amido, -NR42S(O)2-(C1-6)alkyl, -NR42S(O)2-(C3-6)cycloalkyl, -NR42S(O)2-aryL -NR42S(O)2-heteroaryl, -NR42S(O)2-heteroalicyclic, NR42R43 COOH;
G is selected from the group consisting of (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6)alkoxy, (C1-6)thioalkoxy, thioaryloxy, cyano, halogen, nitro, carbonyl, thiocarbonyl, benzyl, -NR48C(O)-(C1-6)alkyl, - NR48C(O)-(C3-6)cycloalkyl, -NR48C(O)-aryl, -NR48C(O)-heteroaryl, -NR48C(O)-heteroalicyclic, a cyclic N-amido, -NR48S(O)2-(C1-6)alkyl, -NR48S(O)2-(C1-6)cycloalkyl, NR48S(O)2-aryl, -NR48S(O)2-heteroaryl, NR48S(O)2-heteroalicyclic, sulfonyl, -S(O)2 NR48R49, NR48R49, (C1-6)alkyl C(O)NR48R49, C(O)NR48R49, NHC(O)NR48R49, OC(O)NR48R49, NHC(O)OR54', (C1-6)alkylNR48R49, COOR54, and (C1-6)alkylCOOR54';
R7 is selected from the group consisting of aryl, heteroaryl, and heteroalicyclic wherein
said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to
three same or different halogens or with from one to two same or different substituents
selected from the group F;
R42 and R43 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic or R42 and R43 taken together with the nitrogen to which they are attached form a heteroaryl ring
or a heteroalicyclic ring which may contain up to two additional heteroatoms selected
from N, O, S(O)m, wherein m' is 0, 1, or 2; and wherein said (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl, (C2-6)alkenyl, (C3-7)cycloalkenyl, (C2-6)alkynyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with one
to three same or different halogens or from one to two same or different substituents
selected from the group G;
R48 and R49 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, (C1-6alkoxy, (C3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic or R48 and R49 taken together with the nitrogen to which they are attached form a heteroaryl ring
or a heteroalicyclic ring which may contain up to two additional heteroatoms selected
from N, O, S(O)m, wherein m' is 0, 1, or 2;
R54 is selected from the group consisting of hydrogen, (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, and heteroalicyclic wherein said (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with
one to three same or different halogens or from one to two same or different substituents
selected from the group consisting of: amino, OH, and NR55R56;
R54' is selected from the group consisting of (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, and heteroalicyclic wherein said (C1-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionally substituted with
one to three same or different halogens or from one to two same or different substituents
selected from the group consisting of: amino, OH, and NR55R56;
R55 and R56 are independently selected from the group consisting of hydrogen, (C1-6)alkyl, or (C3-7)cycloalkyl
[0012] A further group of preferred compounds is those wherein:
Q is

R2 is selected from the group consisting of hydrogen or methoxy;
R3 is hydrogen;
R4 is B
B is heteroaryl, wherein said heteroaryl is optionally substituted with one to three
same or different halogens or from one to two same or different substituents selected
from the group F;
[0013] A final prefixed aspect of the invention are compounds depicted in Table 2 or Table
4 of the biology section.
[0014] A further embodiment is a compound of the present invention for use in a method for
treating mammals infected with a virus, wherein said virus is HIV, comprising administering
to said mammal an antiviral effective amount of a compound of Formula I.
[0015] A further embodiment is a compound of the present invention for use in a method for
treating mammals infected with a virus, such as HIV, comprising administering to said
mammal an antiviral effective amount of a compound of Formula I in combination with
an antiviral effective amount of an AIDS treatment agent selected from the group consisting
of: (a) an AIDS antiviral agent; (b) an anti-infective agent; (c) an immunomodulator,
and (d) HIV entry inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
[0016] Since the compounds of the present invention, may possess asymmetric centers and
therefore occur as mixtures of diastereomers and enantiomers, the present invention
includes the individual diastereoisomeric and enantiomeric forms of the compounds
of Formula I in addition to the mixtures thereof.
DEFINITIONS
[0017] The term "C
1-6 alkyl" as used herein and in the claims (unless specified otherwise) mean straight
or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, amyl, hexyl and the like.
[0018] "Halogen," refers to chlorine, bromine, iodine or fluorine.
[0019] An "aryl" group refers to an all carbon monocyclic or fused-ring polycyclic (i.e.,
rings which share adjacent pairs of carbon atoms) groups having a completely conjugated
pi-electron system. Examples, without limitation, of aryl groups are phenyl napthalenyl
and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted
the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl,
aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy,
thiohydroxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,
nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl,
sulfonyl, sulfonamido, trihalomethyl, ureido, amino and -NR
xR
y, wherein R
x and R
y are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,
aryl, carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- or six-member
heteroalicyclic ring.
[0020] As used herein, a "heteroaryl" group refers to a monocyclic or fused ring (i.e.,
rings which share an adjacent pair of atoms) group having in the ring(s) one or more
atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition,
having a completely conjugated pi-electron system. It should be noted that the term
heteroaryl is intended to encompass an N-oxide of the parent heteroaryl if such an
N-oxide is chemically feasible as is known in the art. Examples, without limitation,
of heteroaryl groups are furyl, thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl,
oxadiazolyl, thiadiazolyl, benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,
pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl,
isoquinolinyl, purinyl, carbazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl,
pyrazinyl. diazinyl, pyrazine, triazinyltriazine, tetrazinyl, and tetrazolyl. When
substituted the substituted group(s) is preferably one or more selected from alkyl,
cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,
heteroalicycloxy, thiohydroxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy,
cyano, halogen, nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,
O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino, and -NR
xR
y, wherein R
x and R
y are as defined above.
[0021] As used herein, a "heteroalicyclic" group refers to a monocyclic or fused ring group
having in the ring(s) one or more atoms selected from the group consisting of nitrogen,
oxygen and sulfur. The rings may also have one or more double bonds. However, the
rings do not have a completely conjugated pi-electron system. Examples, without limitation,
of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl, imidazolinyl, thiazolidinyl,
3-pyrrolidin-1-yl, morpholinyl, thiomorpholinyl and tetrahydropyranyl. When substituted
the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl,
aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy,
thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano,
halogen, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,
C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido,
trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido,
phosphonyl, amino and -NR
xR
y, wherein R
x and R
y are as defined above.
[0022] An "alkyl" group refers to a saturated aliphatic hydrocarbon including straight chain
and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms (whenever
a numerical range; e.g., "1-20", is stated herein, it means that the group, in this
case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc.
up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having
1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms.
The alkyl group may be substituted or unsubstituted. When substituted, the substituent
group(s) is preferably one or more individually selected from trihaloalkyl, cycloalkyl,
aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy,
thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano,
halo, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,
C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido,
trihalomethanesulfonamido, trihalomethanesulfonyl, and combined, a five- or six-member
heteroalicyclic ring.
[0023] A "cycloalkyl" group refers to an all-carbon monocyclic or fused ring (i.e., rings
which share and adjacent pair of carbon atoms) group wherein one or more rings does
not have a completely conjugated pi-electron system. Examples, without limitation,
of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,
cyclohexadiene, cycloheptane, cycloheptatriene and adamantane. A cycloalkyl group
may be substituted or unsubstituted. When substituted, the substituent group(s) is
preferably one or more individually selected from alkyl, aryl, heteroaryl, heteroalicyclic,
hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy,
thioaryloxy, thioheteroarylloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,
thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido,
N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalo- methanesulfonamido,
trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl, amino and -
NR
xR
y with R
x and R
y as defined above.
[0024] An "alkenyl" group refers to an alkyl group, as defined herein, consisting of at
least two carbon atoms and at least one carbon-carbon double bond.
[0025] An "alkynyl" group refers to an alkyl group, as defined herein, consisting of at
least two carbon atoms and at least one carbon-carbon triple bond.
[0026] A "hydroxy" group refers to an -OH group.
[0027] An "alkoxy" group refers to both an -O-alkyl and an -O-cycloalkyl group as defined
herein.
[0028] An "aryloxy" group refers to both an -0-aryl and an -0-heteroaryl group, as defined
herein.
[0029] A "heteroaryloxy" group refers to a heteroaryl-O- group with heteroaryl as defined
herein.
[0030] A "heteroalicycloxy" group refers to a heteroalicyclic-O- group with heteroalicyclic
as defined herein.
[0031] A "thiohydroxy" group refers to an -SH group.
[0032] A "thioalkoxy" group refers to both an S-alkyl and an -S-cycloalkyl group, as defined
herein.
[0033] A "thioaryloxy" group refers to both an -S-aryl and an -S-heteroaryl group, as defined
herein.
[0034] A "thioheteroaryloxy" group refers to a heteroaryl-S- group with heteroaryl as defined
herein.
[0035] A "thioheteroalicycloxy" group refers to a heteroalicyclic-S- group with heteroalicyclic
as defined herein.
[0036] A "carbonyl" group refers to a -C(=O)-R" group, where R" is selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl (bonded
through a ring carbon) and heteroalicyclic (bonded through a ring carbon), as each
is defined herein.
[0037] An "aldehyde" group refers to a carbonyl group where R" is hydrogen.
[0038] A "thiocarbonyl" group refers to a -C(=S)-R" group, with R" as defined herein.
[0039] A "Keto" group refers to a -CC(=O)C- group wherein the carbon on either or both sides
of the C=O may be alkyl, cycloalkyl, aryl or a carbon of a heteroaryl or heteroaliacyclic
group.
[0040] A "trihalomethanecarbonyl" group refers to a Z
3CC(=O)- group with said Z being a halogen.
[0041] A "C-carboxy" group refers to a -C(=O)O-R" groups, with R" as defined herein.
[0042] An "O-carboxy" group refers to a R"C(-O)O-group, with R" as defined herein.
[0043] A "carboxylic acid" group refers to a C-carboxy group in which R" is hydrogen.
[0044] A "trihalomethyl" group refers to a -CZ
3, group wherein Z is a halogen group as defined herein.
[0045] A "trihalomethanesulfonyl" group refers to an Z
3CS(=O)
2- groups with Z as defined above.
[0046] A "trihalomethanesulfonamido" group refers to a Z
3CS(=O)
2NR
x- group with Z and R
x as defined herein.
[0047] A "sulfinyl" group refers to a -S(=O)-R" group, with R" as defined herein and, in
addition, as a bond only; i.e., -S(O)-.
[0048] A "sulfonyl" group refers to a -S(=O)
2R" group with R" as defmed herein and, in addition as a bond only; i.e., -S(O)
2-.
[0049] A "S-sulfonamido" group refers to a -S(=O)2NR
XR
Y, with R
X and R
Y as defined herein.
[0050] A "N-Sulfonamido" group refers to a R"S(=O)
2NR
x- group with R
x as defined herein.
[0051] A "O-carbamyl" group refers to a -OC(=O)NR
xR
y as defined herein.
[0052] A "N-carbamyl" group refers to a R
xOC(=O)NR
y group, with R
x and R
y as defined herein.
[0053] A "O-thiocarbamyl" group refers to a -OC(=S)NR
xR
y group with R
x and R
y as defined herein.
[0054] A "N-thiocarbamyl" group refers to a R
xOC(=S)NR
y- group with R
x and R
y as defined herein.
[0055] An "amino" group refers to an NH
2 group.
[0056] A "C-amido" group refers to a -C(=O)NR
xR
y group with R
x and R
y as defined herein.
[0057] A "C-thioamido" group refers to a -C(=S)NR
xR
y group, with R
x and R
y as defined herein.
[0058] A "N-amido" group refers to a R
xC(=O)NR
y- group, with R
x and R
y as defined herein.
[0059] An "ureido" group refers to a -NR
xC(=O)NR
yR
y2 group with R
x and R
y as defined herein and R
y2 defined the same as R
x and R
y.
[0060] A "guanidino" group refers to a -R
xNC(=N)NR
yR
y2 group, with R
x, R
y and R
y2 as defined herein.
[0061] A "guanyl" group refers to a R
xR
yNC(=N)- group, with R
x and R
Y as defined herein.
[0062] A "cyano" group refers to a-CN group.
[0063] A "silyl" group refers to a -Si(R")
3, with R" as defined herein.
[0064] A "phosphonyl" group refers to a P(=O)(OR
x)
2 with R
x as defined herein.
[0065] A "hydrazino" group refers to a NR
xNR
yR
y2 group with R
x, R
y and R
y2 as defined herein.
[0066] Any two adjacent R groups may combine to form an additional aryl, cycloalkyl, heteroaryl
or heterocyclic ring fused to the ring initially bearing those R groups.
[0067] It is known in the art that nitogen atoms in heteroaryl systems can be "participating
in a heteroaryl ring double bond", and this refers to the form of double bonds in
the two tautomeric structures which comprise five-member ring heteroaryl groups. This
dictates whether nitrogens can be substituted as well understood by chemists in the
art. The disclosure and claims of the present invention are based on the known general
principles of chemical bonding. It is understood that the claims do not encompass
structures known to be unstable or not able to exist based on the literature.
[0068] Physiologically acceptable salts and prodrugs of compounds disclosed herein are within
the scope of this invention. The term "pharmaceutically acceptable salt" as used herein
and in the claims is intended to include nontoxic base addition salts. Suitable salts
include those derived from organic and inorganic acids such as, without limitation,
hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic
acid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citric acid, maleic
acid, fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, and
the like. The term "pharmaceutically acceptable salt" as used herein is also intended
to include salts of acidic groups, such as a carboxylate, with such counterions as
ammonium, alkali metal salts, particularly sodium or potassium, alkaline earth metal
salts, particularly calcium or magnesium, and salts with suitable organic bases such
as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with
substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such as diethanolamine,
triethanolamine or tris(hydroxymethyl)- aminomethane), or with bases such as piperidine
or morpholine.
[0069] In the method of the present invention, the term "antiviral effective amount" means
the total amount of each active component of the method that is sufficient to show
a meaningful patient benefit, i.e., healing of acute conditions characterized by inhibition
of the HIV infection. When applied to an individual active ingredient, administered
alone, the term refers to that ingredient alone. When applied to a combination, the
term refers to combined amounts of the active ingredients that result in the therapeutic
effect, whether administered in combination, serially or simultaneously. The terms
"treat, treating, treatment" as used herein and in the claims means preventing or
ameliorating diseases associated with HIV infection.
[0070] The present invention is also directed to combinations of the compounds with one
or more agents useful in the treatment of AIDS. For example, the compounds of this
invention may be effectively administered, whether at periods of pre-exposure and/or
post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators,
antiinfectives, or vaccines, such as those in the following table.
ANTIVIRALS
[0071]
Drug Name |
Manufacturer |
Indication |
097 |
Hoechst/Bayer |
HIV infection, |
|
|
AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor) |
|
|
|
Amprenivir |
Glaxo Wellcome |
HIV infection, |
141 W94 |
|
AIDS, ARC |
GW 141 |
|
(protease inhibitor) |
|
|
|
Abacavir (1592U89) |
Glaxo Wellcome |
HIV infection, |
GW 1592 |
|
AIDS, ARC |
|
|
(RT inhibitor) |
|
|
|
Acemannan |
Carrington Labs (Irving, TX) |
ARC |
|
|
|
Acyclovir |
Burroughs Wellcome |
HIV infection, AIDS, |
|
|
ARC, in combination with AZT |
|
|
|
AD-439 |
Tanox Biosystems |
HIV infection, AIDS, |
|
|
ARC |
AD-519 |
Tanox Biosystems |
HIV infection, AIDS, |
|
|
ARC |
|
|
|
Adefovir dipivoxil |
Gilead Sciences |
HIV infection |
AL-721 |
Ethigen |
ARC, PGL |
|
(Los Angeles, CA) |
HIV positive, AIDS |
|
|
|
Alpha Interferon |
Glaxo Wellcome |
Kaposi's sarcoma, |
|
|
HIV in combination w/Retrovir |
|
|
|
Ansamycin |
Adria Laboratories |
ARC |
LM 427 |
(Dublin, OH) |
|
|
Erbamont |
|
|
(Stamford, CT) |
|
|
|
|
Antibody which |
Advanced Biotherapy |
AIDS, ARC |
Neutralizes pH |
Concepts |
|
Labile alpha aberrant |
(Rockville, MD) |
|
Interferon |
|
|
|
|
|
AR177 |
Aronex Pharm |
HIV infection, AIDS, |
|
|
ARC |
|
|
|
Beta-fluoro-ddA |
Nat'l Cancer Institute |
AIDS-associated |
|
|
diseases |
|
|
|
BMS-232623 |
Bristol-Myers Squibb/ |
HIV infection, |
(CGP-73547) |
Novartis |
AIDS, ARC |
|
|
(protease inhibitor) |
|
|
|
BMS-234475 |
Bristol-Myers Squibb/ |
HIV infection, |
(CGP-61755) |
Novartis |
AIDS, ARC |
|
|
(protease inhibitor) |
|
|
|
CI-1012 |
Warner-Lambert |
HIV-1 infection |
|
|
|
Cidofovir |
Gilead Science |
CMV retinitis, |
|
|
herpes, papillomavirus |
|
|
|
Curdlan sulfate |
AJI Pharma USA |
HIV infection |
|
|
|
Cytomegalovirus Immune globin |
MedImmune |
CMV retinitis |
Cytovene |
Syntex |
Sight threatening |
Ganciclovir |
|
CMV |
|
|
peripheral CMV |
|
|
retinitis |
|
|
|
Delaviridine |
Pharmacia-Upjohn |
HIV infection, |
|
|
AIDS, ARC |
|
|
(RT inhibitor) |
|
|
|
Dextran Sulfate |
Ueno Fine Chem. |
AIDS, ARC, HIV |
|
Ind. Ltd. (Osaka, |
positive |
|
Japan) |
asymptomatic |
|
|
|
ddC |
Hoffman-La Roche |
HIV infection, AIDS, |
Dideoxycytidine |
|
ARC |
|
|
|
ddI |
Bristol-Myers Squibb |
HIV infection, AIDS, |
Dideoxyinosine |
|
ARC; combination |
|
|
with AZT/d4T |
|
|
|
DMP-450 |
AVID |
HIV infection, |
|
(Camden, NJ) |
AIDS, ARC |
|
|
(protease inhibitor) |
|
|
|
Efavirenz |
DuPont Merck |
HIV infection, |
(DMP 266) |
|
AIDS, ARC |
(-)6-Chloro-4-(S)-cyclopropylethynyl-4(S)-trifluoro-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one,
STOCRINE |
|
(non-nucleoside RT inhibitor) |
|
|
|
EL10 |
Elan Corp, PLC |
HIV infection |
|
(Gainesville, GA) |
|
|
|
|
Famciclovir |
Smith Kline |
herpes zoster, |
|
|
herpes simplex |
FTC |
Emory University |
HIV infection, |
|
|
AIDS, ARC |
|
|
(reverse transcriptase inhibitor) |
|
|
|
GS 840 |
Gilead |
HIV infection, |
|
|
AIDS, ARC |
|
|
(reverse transcriptase inhibitor) |
|
|
|
HBY097 |
Hoechst Marion |
HIV infection, |
|
Roussel |
AIDS, ARC |
|
|
(non-nucleoside reverse transcriptase inhibitor) |
|
|
|
Hypericin |
VIMRx Pharm. |
HIV infection, AIDS, |
|
|
ARC |
|
|
|
Recombinant Human |
Triton Biosciences |
AIDS, Kaposi's |
Interferon Beta |
(Almeda, CA) |
sarcoma, ARC |
|
|
|
Interferon alfa-n3 |
Interferon Sciences |
ARC, AIDS |
|
|
|
Indinavir |
Merck |
HIV infection, AIDS, |
|
|
ARC, asymptomatic |
|
|
HIV positive, also in combination with |
|
|
AZT/ddI/ddC |
|
|
|
ISIS 2922 |
ISIS Pharmaceuticals |
CMV retinitis |
|
|
|
KNI-272 |
Nat'l Cancer Institute |
HIV-assoc. diseases |
|
|
|
Lamivudine, 3TC |
Glaxo Wellcome |
HIV infection, |
|
|
AIDS, ARC |
|
|
(reverse transcriptase inhibitor); also with AZT |
Lobucavir |
Bristol-Myers Squibb |
CMV infection |
Nelfinavir |
Agouron |
HIV infection, |
|
Pharmaceuticals |
AIDS, ARC |
|
|
(protease inhibitor) |
|
|
|
Nevirapine |
Boeheringer |
HIV infection, |
|
Ingleheim |
AIDS, ARC |
|
|
(RT inhibitor) |
|
|
|
Novapren |
Novaferon Labs, Inc. (Akron, OH) |
HIV inhibitor |
|
|
|
Peptide T |
Peninsula Labs |
AIDS |
Octapeptide |
(Belmont, CA) |
|
Sequence |
|
|
|
|
|
Trisodium |
Astra Pharm. |
CMV retinitis, HIV |
Phosphonoformate |
Products, Inc. |
infection, other CMV |
|
|
infections |
|
|
|
PNU-140690 |
Pharmacia Upjohn |
HIV infection, |
|
|
AIDS, ARC |
|
|
(protease inhibitor) |
|
|
|
Probucol |
Vyrex |
HIV infection, AIDS |
|
|
|
RBC-CD4 |
Sheffield Med. |
HIV infection, |
|
Tech (Houston, TX) |
AIDS, ARC |
|
|
|
Ritonavir |
Abbott |
HIV infection, |
|
|
AIDS, ARC |
|
|
(protease inhibitor) |
|
|
|
Saquinavir |
Hoffmann- |
HIV infection, |
|
LaRoche |
AIDS, ARC |
|
|
(protease inhibitor) |
|
|
|
Stavudine; d4T |
Bristol-Myers Squibb |
HIV infection, AIDS, |
Didehydrodeoxy- |
|
ARC |
thymidine |
|
|
|
|
|
Valaciclovir |
Glaxo Wellcome |
Genital HSV & CMV infections |
Virazole |
Viratek/ICN |
asymptomatic HIV |
Ribavirin |
(Costa Mesa, CA) |
positive, LAS, ARC |
|
|
|
VX-478 |
Vertex |
HIV infection, AIDS, |
|
|
ARC |
|
|
|
Zalcitabine |
Hoffmann-LaRoche |
HIV infection, AIDS, |
|
|
ARC, with AZT |
|
|
|
Zidovudine; AZT |
Glaxo Wellcome |
HIV infection, AIDS, |
|
|
ARC, Kaposi's |
|
|
sarcoma, in combination with |
|
|
other therapies |
|
|
|
IMMUNOMODULATORS |
Drug Name |
Manufacturer |
Indication |
AS-101 |
Wyeth-Ayerst |
AIDS |
Bropirimine |
Pharmacia Upjohn |
Advanced AIDS |
Acemannan |
Carrington Labs, Inc. (Irving, TX) |
AIDS, ARC |
CL246,738 |
American Cyanamid Lederle Labs |
AIDS, Kaposi's sarcoma |
EL 10 |
Elan Corp, PLC (Gainesville, GA) |
HIV infection |
FP-21399 |
Fuki ImmunoPharm |
Blocks HIV fusion with CD4+ cells |
Gamma Interferon |
Genentech |
ARC, in combination |
|
|
w/TNF (tumor necrosis factor) |
|
|
|
Granulocyte |
Genetics Institute |
AIDS |
Macrophage Colony |
Sandoz |
|
Stimulating Factor |
|
|
|
|
|
Granulocyte |
Hoechst-Roussel |
AIDS |
Macrophage Colony |
Immunex |
|
Stimulating Factor |
|
|
|
|
|
Granulocyte |
Schering-Plough |
AIDS, |
Macrophage Colony |
|
combination |
Stimulating Factor |
|
w/AZT |
|
|
|
HIV Core Particle |
Rorer |
Seropositive HIV |
Immunostimulant |
|
|
|
|
|
IL-2 |
Cetus |
AIDS, in combination |
Interleukin-2 |
|
w/AZT |
|
|
|
IL-2 |
Hoffman-LaRoche |
AIDS, ARC, HIV, in |
Interleukin-2 |
Immunex |
combination w/AZT |
|
|
|
IL-2 |
Chiron |
AIDS, increase in |
Interleukin-2 |
|
CD4 cell counts |
(aldeslukin) |
|
|
|
|
|
Immune Globulin |
Cutter Biological |
Pediatric AIDS, in |
Intravenous |
(Berkeley, CA) |
combination w/AZT |
(human) |
|
|
|
|
|
IMREG-1 |
Imreg |
AIDS, Kaposi's |
|
(New Orleans, LA) |
sarcoma, ARC, PGL |
|
|
|
IMREG-2 |
Imreg |
AIDS, Kaposi's |
|
(New Orleans, LA) |
sarcoma, ARC, PGL |
|
|
|
Imuthiol Diethyl |
Merieux Institute |
AIDS, ARC |
Dithio Carbamate |
|
|
|
|
|
Alpha-2 |
Schering Plough |
Kaposi's sarcoma |
Interferon |
|
w/AZT, AIDS |
Methionine- |
TNI Pharmaceutical |
AIDS, ARC |
Enkephalin |
(Chicago, IL) |
|
|
|
|
MTP-PE |
Ciba-Geigy Corp. |
Kaposi's sarcoma |
Muramyl-Tripeptide |
|
|
|
|
|
Granulocyte |
Amgen |
AIDS, in combination |
Colony Stimulating |
|
w/AZT |
Factor |
|
|
|
|
|
Remune |
Immune Response |
Immunotherapeutic |
|
Corp. |
|
|
|
|
rCD4 |
Genentech |
AIDS, ARC |
Recombinant |
|
|
Soluble Human CD4 |
|
|
|
|
|
rCD4-IgG |
|
AIDS, ARC |
hybrids |
|
|
|
|
|
Recombinant |
Biogen |
AIDS, ARC |
Soluble Human CD4 |
|
|
|
|
|
Interferon |
Hoffman-La Roche |
Kaposi's sarcoma |
Alfa 2a |
|
AIDS, ARC, |
|
|
in combination w/AZT |
|
|
|
SK&F 106528 |
Smith Kline |
HIV infection |
Soluble T4 |
|
|
|
|
|
Thymopentin |
Immunobiology |
HIV infection |
|
Research Institute |
|
|
(Annandale, NJ) |
|
|
|
|
Tumor Necrosis |
Genentech |
ARC, in combination |
Factor; TNF |
|
w/gamma Interferon |
ANTI-INFECTIVES
[0072]
Drug Name |
Manufacturer |
Indication |
Clindamycin with |
Pharmacia Upjohn |
PCP |
Primaquine |
|
|
|
|
|
Fluconazole |
Pfizer |
Cryptococcal |
|
|
meningitis, |
|
|
candidiasis |
|
|
|
Pastille |
Squibb Corp. |
Prevention of |
Nystatin Pastille |
|
oral candidiasis |
|
|
|
Ornidyl |
Merrell Dow |
PCP |
Eflornithine |
|
|
|
|
|
Pentamidine |
LyphoMed |
PCP treatment |
Isethionate (IM & IV) |
(Rosemont, IL) |
|
|
|
|
Trimethoprim |
|
Antibacterial |
|
|
|
Trimethoprim/sulfa |
|
Antibacterial |
|
|
|
Piritrexim |
Burroughs Wellcome |
PCP treatment |
|
|
|
Pentamidine |
Fisons Corporation |
PCP prophylaxis |
Isethionate for |
|
|
Inhalation |
|
|
|
|
|
Spiramycin |
Rhone-Poulenc |
Cryptosporidial |
|
diarrhea |
|
|
|
|
Intraconazole- |
Janssen-Pharm. |
Histoplasmosis; |
R51211 |
|
cryptococcal |
|
|
meningitis |
|
|
|
Trimetrexate |
Warner-Lambert |
PCP |
Daunorubicin |
NeXstar, Sequus |
Kaposi's sarcoma |
|
|
|
Recombinant Human |
Ortho Pharm. Corp. |
Severe anemia |
Erythropoietin |
|
assoc. with AZT |
|
|
therapy |
|
|
|
Recombinant Human |
Serono |
AIDS-related |
Growth Hormone |
|
wasting, cachexia |
|
|
|
Megestrol Acetate |
Bristol-Myers Squibb |
Treatment of |
|
|
anorexia assoc. |
|
|
W/AIDS |
|
|
|
Testosterone |
Alza, Smith Kline |
AIDS-related wasting |
|
|
|
Total Enteral |
Norwich Eaton |
Diarrhea and |
Nutrition |
Pharmaceuticals |
malabsorption |
|
|
related to AIDS |
[0073] Additionally, the compounds of the invention herein may be used in combination with
another class of agents for treating AIDS which are called HIV entry inhibitors. Examples
of such HIV entry inhibitors are discussed in
DRUGS OF THE FUTURE 1999,24(12), pp. 1355-1362;
CELL, Vol. 9, pp. 243-246, Oct. 29, 1999; and
DRUG DISCOVERY TODAY, Vol. 5, No. 5, May 2000, pp. 183-194.
[0074] It will be understood that the scope of combinations of the compounds of this invention
with AIDS antivirals, immunomodulators, anti-infectives, HIV entry inhibitors or vaccines
is not limited to the list in the above Table, but includes in principle any combination
with any pharmaceutical composition useful for the treatment of AIDS.
[0075] Preferred combinations are simultaneous or alternating treatments of with a compound
of the present invention and an inhibitor of HIV protease and/or a non-nucleoside
inhibitor of HIV reverse transcriptase. An optional fourth component in the combination
is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI.
A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide
ethanolate, and is synthesized according to
U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other
preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor
of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg
tid. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz.
The preparation of ddC, ddI and AZT are also described in
EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree
of infection of HIV. Preferred combinations include those with the following (1) indinavir
with efavirenz, and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir,
and any of AZT and/or ddI and/or ddC and/or 3TC, in particular, indinavir and AZT
and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and
141W94 and 1592U89; (5) zidovudine and lamivudine.
[0076] In such combinations the compound of the present invention and other active agents
may be administered separately or in conjunction. In addition, the administration
of one element may be prior to, concurrent to, or subsequent to the administration
of other agent(s).
[0077] The preparative procedures and anti-HIV-1 activity of the novel azaindole piperazine
diamide analogs of Formula I are summarized below in Schemes 1-64.
Abbreviations
[0078] The following abbreviations, most of which are conventional abbreviations well known
to those skilled in the art, are used throughout the description of the invention
and the examples. Some of the abbreviations used are as follows:
- h
- = hour(s)
- rt
- = room temperature
- mol
- = mole(s)
- mmol
- = millimole(s)
- g
- = gram(s)
- mg
- = milligram(s)
- mL
- = milliliter(s)
- TFA
- = Trifluoroacetic Acid
- DCE
- = 1,2-Dichloroethane
- CH2Cl2
- = Dichloromethane
- TPAP
- = tetrapropylanunonium perruthenate
- THF
- = Tetrahydofuran
- DEPBT
- = 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one
- DMAP
- = 4-dimethylaminopyridine
- P-EDC
- = Polymer supported 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
- EDC
- = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
- DMF
- = N,N-dimethylformamide
- Hunig's Base
- = N,N-Diisopropylethylamine
- mCPBA
- = meta-Chloroperbenzoic Acid
- azaindole
- = 1H-Pyrrolo-pyridine
- 4-azaindole
- = 1H-pyrrolo[3,2-b]pyridine
- 5-azaindole =
- 1H-Pyrrolo[3,2-c]pyridine
- 6-azaindole
- = 1H-pyrrolo[2,3-c]pyridine
- 7-azaindole
- = 1H-Pyrrolo[2,3-b]pyridine
- PMB
- = 4-Methoxybenzyl
- DDQ
- = 2, 3-Dichloro-5, 6-dicyano-1, 4-benzoquinone
- OTf
- = Trifluoromethanesulfonoxy
- NMM
- = 4-Methylmorpholine
- PIP-COPh
- = 1-Benzoylpiperazine
- NaHMDS
- = Sodium hexamethyldisilazide
- EDAC
- = 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
- TMS
- = Trimethylsilyl
- DCM
- = Dichloromethane
- DCE
- = Dichloroethane
- MeOH
- = Methanol
- THF
- = Tetrahrdrofuran
- EtOAc
- = Ethyl Acetate
- LDA
- = Lithium diisopropylamide
- TMP-Li
- = 2,2,6,6-tetramethylpiperidinyl lithium
- DME
- = Dimethoxyethane
- DIBALH
- = Diisobutylaluminum hydride
- HOBT
- = 1-hydroxybenzotriazole
- CBZ
- = Benzyloxycarbonyl
- PCC
- = Pyridinium chlorochromate
Chemistry
[0079] The present invention comprises compounds of Formula I, their pharmaceutical formulations,
and their use in patients suffering from or susceptible to HIV infection. The compounds
of Formula I include pharmaceutically acceptable salts thereof.
[0080] General procedures to construct substituted azaindole piperazine diamides of Formula
I and intermediates useful for their synthesis are described in the following Schemes.

[0081] Step A in Scheme 1 depicts the synthesis of an aza indole intermediate, 2, via the
well known Bartoli reaction in which vinyl magnesium bromide reacts with an aryl or
heteroaryl nitro group, such as in 1, to form a five-membered nitrogen containing
ring as shown. Some references for the above transformation include:
Bartoli et al. a) Tetrahedron Lett. 1989, 30, 2129. b) J. Chem. Soc. Perkin Trans. 1 1991, 2757. c)
J. Chem. Soc. Perkin Trans. II 1991, 657. d)
Synthesis (1999), 1594. In the preferred procedure, a solution of vinyl Magnesium bromide in THF (typically
1.0M but from 0.25 to 3.0M) is added dropwise to a solution of the nitro pyridine
in THF at -78° under an inert atmosphere of either nitrogen or Argon. After addition
is completed, the reaction temperature is allowed to warm to -20° and then is stirred
for approximately 12h before quenching with 20% aq ammonium chloride solution. The
reaction is extracted with ethyl acetate and then worked up in a typical manner using
a drying agent such as anhydrous magnesium sulfate or sodium sulfate. Products are
generally purified using chromatography over Silica gel. Best results are generally
achieved using freshly prepared vinyl Magnesium bromide. In some cases, vinyl Magnesium
chloride may be substituted for vinyl Magnesium bromide.
[0082] Substituted azaindoles may be prepared by methods described in the literature or
may be available from commercial sources. Thus there are many methods for carrying
out step A in the literature and the specific examples are too numerous to even list
Alternative syntheses of aza indoles and general methods for carrying out step A include,
but are not limited to, those described in the following references (a-k below): a)
Prokopov, A. A.; Yakhontov, L. N. Khim.-Farm. Zh. 1994, 28(7), 30-51; b)
Lablache-Combier, A. Heteroaromatics. Photoinduced Electron Transfer 1988, Pt. C,
134-312; c)
Saify, Zafar Said. Pak. J. Pharmacol. 1986, 2(2), 43-6; d)
Bisagni, E. Jerusalem Symp. Quantum Chem. Biochem. 1972, 4, 439-45; e)
Yakhontov, L. N. Usp. Khim. 1968, 37(7), 1258-87; f)
Willette, R. E. Advan. Heterocycl. Chem. 1968, 9, 27-105; g)
Mahadevan, I.; Rasmussen, M. Tetrahedron 1993, 49(33), 7337-52; h)
Mahadevan, I.; Rasmussen, M. J. Heterocycl. Chem. 1992, 29(2), 359-67; i)
Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H. J. Org. Chem. 1999, 64(26), 9430-9443; j)
Spivey, A.C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998, 39(48), 8919-8922; k)
Advances in Heterocyclic Chemistry (Academic press) 1991, Vol. 52, pg 235-236 and references therein.
[0083] Step B. Intermediate 3 can be prepared by reaction of aza-indole, intermediate 2, with an
excess of CICOCOOMe in the presence of AlCl
3 (aluminum chloride) (Sycheva et al, Ref. 26,
Sycheva, T.V.; Rubtsov, N.M.; Sheinker, Yu.N.; Yakhontov, L.N. Some reactions of 5-cyano-6-chloro-7-azaindoles
and lactam-lactim tautomerism in 5-cyano-6-hydroxy-7-azaindolines. Khim. Geterotsikl.
Soedin., 1987, 100-106). Typically an inert solvent such as CH
2Cl
2 is used but others such as THF, Et
2O, DCE, dioxane, benzene, or toluene may find applicability either alone or in mixtures.
Other oxalate esters such as ethyl or benzyl mono esters of oxalic acid could also
suffice for either method shown above. More lipophilic esters ease isolation during
aqueous extractions. Phenolic or substituted phenolic (such as pentafluorophenol)
esters enable direct coupling of the HW(C=O)A group, such as a piperazine, in Step
D without activation. Lewis acid catalysts, such as tin tetrachloride, titanium IV
chloride, and aluminum chloride are employed in Step B with aluminum chloride being
most preferred. Alternatively, the azaindole is treated with a Grignard reagent such
as MeMgI (methyl magnesium iodide), methyl magnesium bromide or ethyl magnesium bromide
and a zinc halide, such as ZnCl
2 (zinc chloride) or zinc bromide, followed by the addition of an oxalyl chloride mono
ester, such as CICOCOOMe (methyl chlorooxoacetate) or another ester as above, to afford
the aza-indole glyoxyl ester (Shadrina et al, Ref. 25). Oxalic acid esters such as
methyl oxalate, ethyl oxalate or as above are used. Aprotic solvents such as CH
2Cl
2, Et
2O, benzene, toluene, DCE, or the like may be used alone or in combination for this
sequence. In addition to the oxalyl chloride mono esters, oxalyl chloride itself may
be reacted with the azaindole and then further reacted with an appropriate amine,
such as a piperazine derivative (See Scheme 52, for example).
[0084] Step C. Hydrolysis of the methyl ester, (intermediate 3, Scheme 1) affords a potassium salt
of intermediate 4, which is coupled with mono-benzoylated piperazine derivatives as
shown in Step D of Scheme 1. Some typical conditions employ methanolic or ethanolic
sodium hydroxide followed by careful acidification with aqueous hydrochloric acid
of varying molarity but 1M HCl is preferred. The acidification is not utilized in
many cases as described above for the preferred conditions. Lithium hydroxide or potassium
hydroxide could also be employed and varying amounts of water could be added to the
alcohols. Propanols or butanols could also be used as solvents. Elevated temperatures
up to the boiling points of the solvents may be utilized if ambient temperatures do
not suffice. Alternatively, the hydrolysis may be carried out in a non polar solvent
such as CH
2Cl
2 or THF in the presence of Triton B. Temperatures of -78 °C to the boiling point of
the solvent may be employed but -10 °C is preferred. Other conditions for ester hydrolysis
are listed in reference 41 and both this reference and many of the conditions for
ester hydrolysis are well known to chemists of average skill in the art.
Alternative procedures for step B and C:
Imidazolium Chloroaluminate:
[0085] We found that ionic liquid 1-alkyl-3-alkylimidazolium chloroaluminate is generally
useful in promoting the Friedel-Crafts type acylation of indoles and azaindoles. The
ionic liquid is generated by mixing 1-alkyl-3-alkylimidazolium chloride with aluminium
chloride at room temperature with vigorous stirring. 1:2 or 1:3 molar ratio of 1-alkyl-3-alkylimidazolium
chloride to aluminium chloride is preferred. One particular useful imidazolium chloroaluminate
for the acylation of azaindole with methyl or ethyl chlorooxoacetate is the 1-ethyl-3-methylimidazolium
chloroaluminate. The reaction is typically performed at ambient temperature and the
azaindoleglyoxyl ester can be isolated. More conveniently, we found that the glyoxyl
ester can be hydrolyzed
in situ at ambient temperature on prolonged reaction time (typically overnight) to give the
corresponding glyoxyl acid for amide formation
(Scheme 1).

[0086] A representative experimental procedure is as follows: 1-ethyl-3-methylimidazolium
chloride (2 equiv.; purchased from TCI; weighted under a stream of nitrogen) was stirred
in an oven-dried round bottom flask at r.t. under a nitrogen atmosphere, and added
aluminium chloride (6 equiv.; anhydrous powder packaged under argon in ampules purchased
from Aldrich preferred; weighted under a stream of nitrogen). The mixture was vigorously
stirred to form a liquid, which was then added azaindole (1 equiv.) and stirred until
a homogenous mixture resulted. The reaction mixture was added dropwise ethyl or methyl
chlorooxoacetate (2 equiv.) and then stirred at r.t. for 16 h. After which time, the
mixture was cooled in an ice-water bath and the reaction quenched by carefully adding
excess water. The precipitates were filtered, washed with water and dried under high
vacuum to give the azaindoleglyoxyl acid. For some examples, 3 equivalents of 1-ethyl-3-methylimidazolium
chloride and chlorooxoacetate may be required.
[0088] Step D. The acid intermediate, 4, from step C of Scheme 1 is coupled with an amine A(C=O)WH
preferably in the presence of DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3
H)-one) and
N,N-diisopropylethylamine, commonly known as Hunig's base, to provide azaindole piperazine
diamides. DEPBT was prepared according to the procedure of Ref. 28,
Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M. Organic Lett., 1999,
1, 91-93. Typically an inert solvent such as DMF or THF is used but other aprotic solvents
could be used. The group W as referred to herein is

[0089] The amide bond construction reaction could be carried out using the preferred conditions
described above, the EDC conditions described below, other coupling conditions described
in this application, or alternatively by applying the conditions or coupling reagents
for amide bond construction described later in this application for construction of
substituents R
1-R
4. Some specific nonlimiting examples are given in this application.
[0090] The mono-substituted piperazine derivatives can be prepared according to well established
procedures such as those described by Desai et al, Ref. 27(a), Adamczyk et al, Ref.
27(b), Rossen et al, Ref. 27(c), and Wang et al, 27(d).
[0091] Additional procedures for synthesizing, modifying and attaching groups : (C=O)
m-WC(O)-A are contained in
PCT WO 00/71535.

[0092] Scheme 2 provides a more specific example of the transformations previously described
in Scheme 1. Intermediates 6-10 are prepared by the methodologies as described for
intermediates 1a-5a in Scheme 1. Scheme 2A is another embodiment of the transformations
described in Schemes 1 and 2. Conversion of the phenol to the chloride (Step S, Scheme
2A) may be accomplished according to the procedures described in
Reimann, E.; Wichmann, P.; Hoefner, G.; Sci. Pharm. 1996, 64(3), 637-646; and
Katritzky, A.R.; Rachwal, S.; Smith, T.P.; Steel, P.J.; J. Heterocycl. Chem. 1995,
32(3), 979-984. Step T of Scheme 2A can be carried out as described for Step A of Scheme 1. The
bromo intermediate can then be converted into alkoxy, chloro, or fluoro intermediates
as shown in Step U of Scheme 2A. Scheme 2A describes the preferred method for preparing
intermediate 6c or other closely related compounds containing a 4 methoxy group in
the 6-azaindole system. When step U is the conversion of the bromide into alkoxy derivatives,
the conversion may be carried out by reacting the bromide with an excess of sodium
methoxide in methanol with cuprous salts, such as copper I bromide, copper I iodide,
and copper I cyanide. The temperature may be carried out at temperatures of between
ambient and 175° but most likely will be around 115°C or 100°C. The reaction may be
run in a pressure vessel or sealed tube to prevent escape of volatiles such as methanol.
The preferred conditions utilize 3eq of sodium methoxide in methanol, CuBr as the
reaction catalyst (0.2 to 3 equivalents with the preferred being 1 eq or less), and
a reaction temperature of 115° C. The reaction is carried out in a sealed tube or
sealed reaction vessel. The conversion of the bromide into alkoxy derivatives may
also be carried out according to procedures described in
Palucki, M.; Wolfe, J.P.; Buchwald, S.L.; J. Am. Chem. Soc. 1997, 119(14), 3395-3396;
Yamato, T.; Komine, M.; Nagano, Y.; Org. Prep. Proc. Int. 1997, 29(3), 300-303;
Rychnovsky, S.D.; Hwang, K.; J. Org. Chem. 1994, 59(18), 5414-5418. Conversion of the bromide to the fluoro derivative (Step U, Scheme 2A) may be accomplished
according to
Antipin, I.S.; Vigalok, A.I.; Konovalov, A.I.; Zh. Org. Khim. 1991, 27(7), 1577-1577; and
Uchibori, Y.; Umeno, M.; Seto, H.; Qian, Z.; Yoshioka, H.; Synlett. 1992, 4, 345-346. Conversion of the bromide to the chloro derivative (Step U, Scheme 2A) may be accomplished
according to procedures described in
Gilbert, E.J.; Van Vranken, D.L.; J. Am. Chem. Soc. 1996, 118(23), 5500-5501;
Mongin, F.; Mongin, O.; Trecourt, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett.
1996, 37(37), 6695-6698; and
O'Connor, K.J.; Burrows, C.J.; J. Org. Chem. 1991, 56(3), 1344-1346. Steps V, W and X of Scheme 2A are carried out according to the procedures previously
described for Steps B, C, and D of Scheme 1, respectively. The steps of Scheme 2A
may be carried out in a different order as shown in Scheme 2B and Scheme 2C.

[0093] Scheme 3 shows the synthesis of 4-azaindole derivatives 1b-5b, 5-azaindole derivatives
1c-5c, and 7-azaindole derivatives 1d-5d. The methods used to synthesize 1b-5b, 1c-5c,
and 1d-5d are the same methods described for the synthesis of 1a-5a as described in
Scheme 1. It is understood, for the purposes of Scheme 3, that 1b is used to synthesize
2b-5b, 1c provides 2c-5c and 1d provides 2d-5d.
[0095] An alternative method for carrying out the sequence outlined in steps B-D (shown
in Scheme 5) involves treating an azaindole, such as 11, obtained by procedures described
in the literature or from commercial sources, with MeMgI and ZnCl
2, followed by the addition of ClCOCOCl (oxalyl chloride) in either THF or Et
2O to afford a mixture of a glyoxyl chloride azaindole, 12a, and an acyl chloride azaindole,
12b. The resulting mixture of glyoxyl chloride azaindole and acyl chloride azaindole
is then coupled with mono-benzoylated piperazine derivatives under basic conditions
to afford the products of step D as a mixture of compounds, 13a and 13b, where either
one or two carbonyl groups link the azaindole and group W. Separation via chromatographic
methods which are well known in the art provides the pure 13a and 13b. This sequence
is summarized in Scheme 5, below.

[0096] Scheme 6 depicts a general method for modifying the substituent A. Coupling of H-W-C(O)OtBu
using the conditions described previously for W in Scheme 1, Step D provides Boc protected
intermediate, 15. Intermediate 15 is then deprotected by treatment with an acid such
as TFA, hydrochloric acid or formic acid using standard solvents or additives such
as CH
2Cl
2 , dioxane, or anisole and temperatures between -78 °C and 100 °C. Other acids such
as aq hydrochloric or perchloric may also be used for deprotection. Alternatively
other nitrogen protecting groups on W such as Cbz or TROC, may be utilized and could
be removed via hydrogenation or treatment with zinc respectively. A stable silyl protecting
group such as phenyl dimethylsilyl could also be employed as a nitrogen protecting
group on W and can be removed with fluoride sources such as tetrabutylammonium fluoride.
Finally, the free amine is coupled to acid A-C(O)OH using standard amine-acid coupling
conditions such as those used to attach group W or as shown below for amide formation
on positions R
1-R
4 to provide compound 16.
[0097] Some specific examples of general methods for preparing functionalized azaindoles
or for interconverting functionality on aza indoles which will be useful for preparing
the compounds of this invention are shown in the following sections for illustrative
purposes. It should be understood that this invention covers substituted 4, 5, 6,
and 7 azaindoles and that the methodology shown below may be applicable to all of
the above series while other shown below will be specific to one or more. A typical
practioner of the art can make this distinction when not specifically delineated.
Many methods are intended to be applicable to all the series, particularly functional
group installations or interconversions. For example, a general strategy for providing
further functionality of this invention is to position or install a halide such as
bromo, chloro, or iodo, aldehyde, cyano, or a carboxy group on the azaindole and then
to convert that functionality to the desired compounds. In particular, conversion
to substituted heteroaryl, aryl, and amide groups on the ring are of particular interest.
[0098] General routes for functionalizing azaindole rings are shown in Schemes 7, 8 and
9. As depicted in Scheme 7, the azaindole, 17, can be oxidized to the corresponding
N-oxide derivative, 18, by using mCPBA (meta-Chloroperbenzoic Acid) in acetone or DMF
(eq. 1, Harada et al, Ref. 29 and Antonini et al, Ref. 34). The
N-oxide, 18, can be converted to a variety of substituted azaindole derivatives by
using well documented reagents such as phosphorus oxychloride (POCl
3) (eq. 2, Schneller et al, Ref. 30), tetramethylammonium fluoride (Me
4NF) (eq. 3), Grignard reagents RMgX (R = alkyl or aryl, X = Cl, Br or I) (eq. 4, Shiotani
et al, Ref. 31), trimethylsilyl cyanide (TMSCN) (eq. 5, Minakata et al, Ref. 32) or
Ac
2O (eq. 6, Klemm et al, Ref. 33). Under such conditions, a chlorine (in 19), fluorine
(in 20), nitrile (in 22), alkyl (in 21), aromatic (in 21) or hydroxyl group (in 24)
can be introduced to the pyridine ring. Nitration of azaindole
N-oxides results in introduction of a nitro group to azaindole ring, as shown in Scheme
8 (eq. 7, Antonini et al, Ref. 34). The nitro group can subsequently be displaced
by a variety of nucleophilic agents, such as OR, NR
1R
2 or SR, in a well established chemical fashion (eq. 8, Regnouf De Vains et al, Ref.
35(a), Miura et al, Ref. 35(b), Profft et al, Ref. 35(c)). The resulting N-oxides,
26, are readily reduced to the corresponding azaindole, 27, using phosphorus trichloride
(PCl
3) (eq. 9, Antonini et al, Ref .34 and Nesi et al, Ref. 36). Similarly, nitro-substituted
N-oxide, 25, can be reduced to the azaindole, 28, using phosphorus trichloride (eq.
10). The nitro group of compound 28 can be reduced to either a hydroxylamine (NHOH),
as in 29, (eq. 11, Walser et al, Ref. 37(a) and Barker et al, Ref. 37(b)) or an amino
(NH
2) group, as in 30, (eq. 12, Nesi et al , Ref. 36 and Ayyangar et al, Ref. 38) by carefully
selecting different reducing conditions.

[0099] The alkylation of the nitrogen atom at position 1 of the azaindole derivatives can
be achieved using NaH as the base, DMF as the solvent and an alkyl halide or sulfonate
as alkylating agent, according to a procedure described in the literature (Mahadevan
et al, Ref. 39) (Scheme 9).

[0100] In the general routes for substituting the azaindole ring described above, each process
can be applied repeatedly and combinations of these processes is permissible in order
to provide azaindoles incorporating multiple substituents. The application of such
processes provides additional compounds of Formula I.

[0101] The synthesis of 4-aminoazaindoles which are useful precursors for 4, 5, and/or 7-substituted
azaindoles is shown in Scheme 10 above.
The synthesis of 3, 5-dinitro-4-methylpyridine, 32, is described in the following
two references by Achremowicz et.al.:
Achremowicz, Lucjan. Pr. Nauk Inst. Chem. Org. Fiz. Politech. Wroclaw. 1982, 23, 3-128;
Achremowicz, Lucjan. Synthesis 1975, 10, 653-4. In the first step of Scheme 10, the reaction with dimethylformamide dimethyl acetal
in an inert solvent or neat under conditions for forming Batcho-Leimgruber precursors
provides the cyclization precursor, 33, as shown. Although the step is anticipated
to work as shown, the pyridine may be oxidized to the N-oxide prior to the reaction
using a peracid such as MCPBA or a more potent oxidant like metatrifluoromethyl or
meta nitro peroxy benzoic acids. In the second step of Scheme 10, reduction of the
nitro group using for example hydrogenation over Pd/C catalyst in a solvent such as
MeOH, EtOH, or EtOAc provides the cyclized product, 34. Alternatively the reduction
may be carried out using tin dichloride and HCl, hydrogenation over Raney nickel or
other catalysts, or by using other methods for nitro reduction such as described elsewhere
in this application.
[0102] The amino indole, 34, can now be converted to compounds of Formula I via, for example,
diazotization of the amino group, and then conversion of the diazonium salt to the
fluoride, chloride or alkoxy group. See the discussion of such conversions in the
descriotions for Schemes 17 and 18. The conversion of the amino moiety into desired
functionality could then be followed by installation of the oxoacetopiperazine moiety
by the standard methodology described above. 5 or 7-substitution of the azaindole
can arise from N-oxide formation at position 6 and subsequent conversion to the chloro
via conditions such as POCl
3 in chloroform, acetic anhydride followed by POCl
3 in DMF, or alternatively TsCl in DMF. Literature references for these and other conditions
are provided in some of the later Schemes in this application. The synthesis of 4-bromo-7-hydroxy
or protected hydroxy-4-azaindole is described below as this is a useful precursor
for 4 and/or 7 substituted 6-aza indoles.
[0103] The synthesis of 5-bromo-2-hydroxy-4-methyl-3-nitro pyridine, 35, may be carried
out as described in the following reference:
Betageri, R.; Beaulieu, P.L.; Llinas-Brunet, M; Ferland, J.M.; Cardozo, M.; Moss,
N.; Patel, U.; Proudfoot, J.R. PCT Int. Appl. WO 9931066, 1999. Intermediate 36 is prepared from 35 according to the method as described for Step
1 of Scheme 10. PG is an optional hydroxy protecting group such as triallylsilyl or
the like. Intermediate 37 is then prepared from 36 by the selective reduction of the
nitro group in the presence of bromide and subsequent cyclization as described in
the second step of Scheme 10. Fe(OH)
2 in DMF with catalytic tetrabutylammonium bromide can also be utilized for the reduction
of the nitro group. The bromide may then be converted to fluoride via displacement
with fluoride anions or to other substituents. The compounds are then converted to
compounds of Formula I as above.

[0104] An alternate method for preparing substituted 6-azaindoles is shown below in Schemes
12 and 13. It should be recognized that slight modifications of the route depicted
below are possible. For example, acylation reactions of the 3 position of what will
become the azaindole five membered ring, prior to aromatization of the azaindole,
may be carried out in order to obtain higher yields. In addition to a para-methoxybenzyl
group (PMB), a benzyl group can be carried through the sequence and removed during
azaindole formation by using TsOH, p-Chloranil, in benzene as the oxidant if DDQ is
not optimal. The benzyl intermediate, 38, has been described by
Ziegler et al. in J. Am. Chem. Soc. 1973, 95(22), 7458. The transformation of 38 to 40 is analogous to the transformation described in
Heterocycles 1984, 22, 2313.

[0105] Scheme 13 describes various transformations of intermediate 40 which ultimately provide
compounds of Formula I. The conversions of the phenol moiety to other functionality
at position 4 (R
2 position in Scheme 13) may be carried out by the following methods: 1) conversion
of a phenol to methoxy group with silver oxide and MeI or diazomethane; 2) conversion
of a phenolic hydroxy group to chloro using cat ZnCl
2, and N,N dimethylaniline in CH
2Cl
2 or PCl
5 and POCl
3 together; 3) conversion of a phenolic hydroxy group to fluoro using diethylamine-SF
3 as in
Org.Prep. Proc. Int. 1992, 24(1), 55-57. The method described in
EP 427603, 1991, using the chloroformate and HF will also be useful. Other transformations are possible.
For example the phenol can be converted to a triflate by standard methods and used
in coupling chemistries described later in this application.

[0106] Step E Scheme 14 depicts the nitration of an azaindole, 41, (R
2 = H). Numerous conditions for nitration of the azaindole may be effective and have
been described in the literature. N
2O
5 in nitromethane followed by aqueous sodium bisulfite according to the method of
Bakke, J. M.; Ranes, E.; Synthesis 1997, 3, 281-283 could be utilized. Nitric acid in acetic may also be employed as described in
Kimura, H.; Yotsuya, S.; Yuki, S.; Sugi, H.; Shigehara, I.; Haga, T.; Chem. Pharm.
Bull. 1995, 43(10), 1696-1700. Sulfuric acid followed by nitric acid may be employed as in
Ruefenacht, K.; Kristinsson, H.; Mattern, G.; Helv Chim Acta 1976, 59, 1593.
Coombes, R. G.; Russell, L. W.; J. Chem. Soc., Perkin Trans. 1 1974, 1751 describes the use of a Titatanium based reagent system for nitration. Other conditions
for the nitration of the azaindole can be found in the following references:
Lever, O.W.J.; Werblood, H. M.; Russell, R. K.; Synth. Comm. 1993, 23(9), 1315-1320;
Wozniak, M.; Van Der Plas, H. C.; J. Heterocycl Chem. 1978, 15, 731.

Step F
[0107] As shown above in Scheme 15, Step F, substituted azaindoles containing a chloride,
bromide, iodide, triflate, or phosphonate undergo coupling reactions with a boronate
(Suzuki type reactions) or a stannane to provide substituted azaindoles. Stannanes
and boronates are prepared via standard literature procedures or as described in the
experimental section of this application. The substitututed indoles may undergo metal
mediated coupling to provide compounds of Formula I wherein R
4 is aryl, heteroaryl, or heteroalicyclic for example. The bromoazaindole intermediates,
(or azaindole triflates or iodides) may undergo Stille-type coupling with heteroarylstannanes
as shown in Scheme 15. Conditions for this reaction are well known in the art and
the following are three example references a)
Farina, V.; Roth, G.P. Recent advances in the Stille reaction; Adv. Met.-Org. Chem.
1996, 5, 1-53. b)
Farina, V.; Krishnamurthy, V.; Scott, W.J. The Stille reaction; Org. React. (N. Y.)
1997, 50, 1-652. and c)
Stille, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508-524. Other references for general coupling conditions are also in the reference by
Richard C. Larock Comprehensive Organic Transformations 2nd Ed. 1999, John Wiley and
Sons New York. All of these references provide numerous conditions at the disposal of those skilled
in the art in addition to the specific examples provided in Scheme 15 and in the specific
embodiments. It can be well recognized that an indole stannane could also couple to
a heterocyclic or aryl halide or triflate to construct compounds of Formula I. Suzuki
coupling (
Norio Miyaura and Akiro Suzuki Chem Rev.1995, 95, 2457.) between a triflate, bromo, or chloro azaindole intermediate and a suitable boronate
could also be employed and some specific examples are contained in this application.
Palladium catalyzed couplings of stannanes and boronates between chloro azaindole
intermediates are also feasible and have been utilized extensively for this invention.
Preferred procedures for coupling of a chloro azaindole and a stannane employ dioxane,
stoichiometric or an excess of the tin reagent (up to 5 equivalents), 0.1 to 1 eq
of Palladium (0) tetrakis triphenyl phosphine in dioxane heated for 5 to 15 h at 110
to 120°. Other solvents such as DMF, THF, toluene, or benzene could be employed. Preferred
procedures for Suzuki coupling of a chloro azaindole and a boronate employ 1:1 DMF
water as solvent, 2 equivalents of potassium carbonate as base stoichiometric or an
excess of the boron reagent (up to 5 equivalents), 0.1 to 1 eq of Palladium (0) tetrakis
triphenyl phosphine heated for 5 to 15 h at 110 to 120°. If standard conditions fail
new specialized catalysts and conditions can be employed. Some references (and the
references therein) describing catalysts which are useful for coupling with aryl and
heteroaryl chlorides are:
Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122(17), 4020-4028; Varma, R. S.; Naicker, K. P. Tetrahedron Lett. 1999, 40(3), 439-442; Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59(17), 5034-7; Buchwald, S.; Old, D. W.; Wolfe, J. P.; Palucki, M.; Kamikawa, K.; Chieffi, A.; Sadighi,
J. P.; Singer, R. A.; Ahman, J PCT Int. Appl. WO 0002887 2000; Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38(23), 3415; Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121(41), 9550-9561; Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38(16), 2413-2416; Bracher, F.; Hildebrand, D.; Liebigs Ann. Chem. 1992, 12, 1315-1319; and Bracher, F.; Hildebrand, D.; Liebigs Ann. Chem. 1993, 8, 837-839.
[0108] Alternatively, the boronate or stannane may be formed on the azaindole via methods
known in the art and the coupling performed in the reverse manner with aryl or heteroaryl
based halogens or triflates.
[0109] Known boronate or stannane agents could be either purchased from commercial resources
or prepared following disclosed documents. Additional examples for the preparation
of tin reagents or boronate reagents are contained in the experimental section.
[0111] Related examples are provided in the following experimental section.
[0113] The preparation of a key aldehyde intermediate, 43, using a procedure adapted from
the method of
Gilmore et. Al. Synlett 1992, 79-80. Is shown in Scheme 16 above. The aldehyde substituent is shown only at the R
4 position for the sake of clarity, and should not be considered as a limitation of
the methodology. The bromide or iodide intermediate is converted into an aldehyde
intermediate, 43, by metal-halogen exchange and subsequent reaction with dimethylformamide
in an appropriate aprotic solvent. Typical bases used include, but are not limited
to, alkyl lithium bases such as n-butyl lithium, sec butyl lithium or tert butyl lithium
or a metal such as lithium metal. A preferred aprotic solvent is THF. Typically the
transmetallation is initiated at -78 °C. The reaction may be allowed to warm to allow
the transmetalation to go to completion depending on the reactivity of the bromide
intermediate. The reaction is then recooled to -78 °C and allowed to react with dimethylformamide.
(allowing the reaction to warm may be required to enable complete reaction) to provide
an aldehyde which is elaborated to compounds of . Formula I. Other methods for introduction
of an aldehyde group to form intermediates of formula 43 include transition metal
catalyzed carbonylation reactions of suitable bromo, trifluoromethane sulfonyl, or
stannyl azaindoles. Alternative the aldehydes can be introduced by reacting indolyl
anions or indolyl Grignard reagents with formaldehyde and then oxidizing with MnO
2 or TPAP/NMO or other suitable oxidants to provide intermediate 43.
[0114] The methodology described in
T. Fukuda et.al. Tetrahedron 1999, 55, 9151 and
M. Iwao et. Al. Heterocycles 1992, 34(5), 1031 provide methods for preparing indoles with substituents at the 7-position. The Fukuda
references provide methods for functionalizing the C-7 position of indoles by either
protecting the indole nitrogen with 2,2-diethyl propanoyl group and then deprotonating
the 7-position with sec/Buli in TMEDA to give an anion. This anion may be quenched
with DMF, formaldehyde, or carbon dioxide to give the aldehyde, benzyl alcohol, or
carboxylic acid respectively and the protecting group removed with aqueous t butoxide.
Similar tranformations can be achieved by converting indoles to indoline, lithiation
at C-7 and then reoxidation to the indole such as described in the Iwao reference
above. The oxidation level of any of these products may be adjusted by methods well
known in the art as the interconversion of alcohol, aldehyde, and acid groups has
been well studied. It is also well understood that a cyano group can be readily converted
to an aldehyde. A reducing agent such as DIBALH in hexane such as used in
Weyerstahl, P.; Schlicht, V.; Liebigs Ann/Recl. 1997, 1, 175-177 or alternatively catecholalane in THF such as used in
Cha, J. S.; Chang, S. W.; Kwon, O. O.; Kim, J. M.; Synlett. 1996, 2, 165-166 will readily achieve this conversion to provide intermediates such as 44 (Scheme
16). Methods for synthesizing the nitriles are shown later in this application. It
is also well understood that a protected alcohol, aldehyde, or acid group could be
present in the starting azaindole and carried through the synthetic steps to a compound
of Formula I in a protected form until they can be converted into the desired substituent
at R
1 through R
4. For example, a benzyl alcohol can be protected as a benzyl ether or silyl ether
or other alcohol protecting group; an aldehyde may be carried as an acetal, and an
acid may be protected as an ester or ortho ester until deprotection is desired and
carried out by literature methods.

[0115] Step G Step 1 of Scheme 17 shows the reduction of a nitro group on 45 to the amino group
of 46. Although shown on position 4 of the azaindole, the chemistry is applicable
to other nitro isomers. The procedure described in
Ciurla, H.; Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371 uses hydrazine Raney-Nickel for the reduction of the nitro group to the amine.
Robinson, R. P.; DonahueO, K. M.; Son, P. S.; Wagy, S. D.; J. Heterocyc/. Chem. 1996,
33(2), 287-293 describes the use of hydrogenation and Raney Nickel for the reduction of the nitro
group to the amine. Similar conditions are described by
Nicolai, E.; Claude, S.; Teulon, J. M.; J. Heterocycl. Chem. 1994, 31(1), 73-75 for the same transformation. The following two references describe some trimethylsilyl
sulfur or chloride based reagents which may be used for the reduction of a nitro group
to an amine.
Hwu, J.R.; Wong, F.F.; Shiao, M.J.; J. Org. Chem. 1992, 57(19), 5254-5255;
Shiao, M.J.; Lai, L.L.; Ku, W.S.; Lin, P.Y.; Hwu, J.R.; J. Org. Chem. 1993, 58(17),
4742-4744.
[0116] Step 2 of Scheme 17 describes general methods for conversion of amino groups on azaindoles
into other functionality. Scheme 18 also depicts transformations of an amino azaindole
into various intermediates and compounds of Formula I.
[0117] The amino group at any position of the azaindole, such as 46 (Scheme 17), may be
converted to a hydroxy group using sodium nitrite, sulfuric acid, and water via the
method of
Klemm, L. H.; Zell, R; J. Heterocycl. Chem. 1968, 5, 773.
Bradsher, C. K.; Brown, F. C.; Porter, H. K.; J. Am. Chem. Soc. 1954, 76, 2357 describes how the hydroxy group may be alkylated under standard or Mitsonobu conditions
to form ethers. The amino group may be converted directly into a methoxy group by
diazotization (sodium nitrite and acid )and trapping with methanol.
[0118] The amino group of an azaindole, such as 46, can be converted to fluoro via the method
of Sanchez using HPF
6, NaNO
2, and water by the method described in
Sanchez, J. P.; Gogliotti, R. D.; J. Heterocycl. Chem. 1993, 30(4), 855-859. Other methods useful for the conversion of the amino group to fluoro are described
in
Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett. 1993, 34(18),
2937-2940 and
Sanchez, J. P.; Rogowski, J.W.; J. Heterocycl. Chem. 1987, 24, 215.
[0119] The amino group of the azaindole, 46, can also be converted to a chloride via diazotization
and chloride displacement as described in
Ciurla, H.; Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371 or the methods in
Raveglia, L.F.; Giardina, G.A..; Grugni, M.; Rigolio, R.; Farina, C.; J. Heterocycl.
Chem. 1997, 34(2), 557-559 or the methods in
Matsumoto, J. I.; Miyamoto, T.; Minamida, A.; Mishimura, Y.; Egawa, H.; Mishimura,
H.; J. Med. Chem. 1984, 27(3), 292; or as in
Lee, T.C.; Salemnick, G.; J. Org. Chem.1975, 24, 3608.
[0120] The amino group of the azaindole, 46, can also be converted to a bromide via diazotization
and displacement by bromide as described in
Raveglia, L.F.; Giardina, G.A..; Grugni, M.; Rigolio, R.; Farina, C.; J. Heterocycl.
Chem. 1997, 34(2), 557-559;
Talik, T.; Talik, Z.; Ban-Oganowska, H.; Synthesis 1974, 293; and
Abramovitch, R.A.; Saha, M.; Can. J. Chem. 1966, 44, 1765.

[0121] The preparation of 4-amino 4-azaindole and 7-methyl-4-azaindole is described by
Mahadevan, I.; Rasmussen, M. J. Heterocycl. Chem. 1992, 29(2), 359-67. The amino group of the 4-amino 4-azaindole can be converted to halogens, hydroxy,
protected hydroxy, triflate, as described above in Schemes 17-18 for the 4-amino compounds
or by other methods known in the art. Protection of the indole nitrogen of the 7-methyl-4-azaindole
via acetylation or other strategy followed by oxidation of the 7-methyl group with
potassium permanganate or chromic acid provides the 7-acid /4-N-oxide. Reduction of
the N-oxide, as described below, provides an intermediate from which to install various
substituents at position R
4. Alternatively the parent 4-azaindole which was prepared as described in
Mahadevan, I.; Rasmussen, M. J. Heterocycl. Chem. 1992, 29(2), 359-67 could be derivatized at nitrogen to provide the 1-(2,2-diethylbutanoyl)azaindole
which could then be lithiated using TMEDA /sec BuLi as described in
T. Fukuda et. Al. Tetrahedron 1999, 55, 9151-9162; followed by conversion of the lithio species to the 7-carboxylic acid or 7-halogen
as described. Hydrolysis of the N-amide using aqueous tert-butoxide in THF regenerates
the free NH indole which can now be converted to compounds of Formula I. The chemistry
used to functionalize position 7 can also be applied to the 5 and 6 indole series.
[0122] Scheme 19 shows the preparation of a 7-chloro-4-azaindole, 50, which can be converted
to compounds of Formula I by the chemistry previously described, especially the palladium
catalyzed tin and boron based coupling methodology described above. The chloro nitro
indole, 49, is commercially available or can be prepared from 48 according to the
method of
Delarge, J.; Lapiere, C. L. Pharm. Acta Helv. 1975,50(6),188-91.

[0123] Scheme 20, below, shows another synthetic route to substituted 4-aza indoles. The
3-aminopyrrole, 51, was reacted to provide the pyrrolopyridinone, 52, which was then
reduced to give the hydroxy azaindole, 53. The pyrrolo[2,3-b]pyridines described were
prepared according to the method of
Britten, A.Z.; Griffiths, G.W.G. Chem. Ind. (London) 1973, 6, 278. The hydroxy azaindole, 53, can then be converted to the triflate then further reacted
to provide compounds of Formula I.

[0124] The following references describe the synthesis of 7-halo or 7 carboxylic acid, or
7-amido derivatives of 5-azaindoline which can be used to construct compounds of Formula
I. Bychikhina, N. N.; Azimov, V. A.; Yakhontov, L.N. Khim. Geterotsikl. Soedin. 1983,
1, 58-62;
Bychikhina, N. N.; Azimov, V. A.; Yakhontov, L. N. Khim. Geterotsikl. Soedin. 1982,
3, 356-60;
Azimov, V. A.; Bychikhina, N. N.; Yakhontov, L. N. Khim. Geterotsikl. Soedin. 1981,
12, 1648-53;
Spivey, A.C.; Fekner, T.; Spey, S.E.; Adams, H. J Org. Chem. 1999, 64(26), 9430-9443;
Spivey, A.C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998, 39(48), 8919-8922. The methods described in Spivey et al. (preceding two references) for the preparation
of 1-methyl-7-bromo-4-azaindoline can be used to prepare the 1-benzyl-7-bromo-4-azaindoline,
54, shown below in Scheme 21. This can be utilized in Stille or Suzuki couplings to
provide 55, which is deprotected and dehydrogenated to provide 56. Other useful azaindole
intermediates, such as the cyano derivatives, 57 and 58, and the aldehyde derivatives,
59 and 60, can then be further elaborated to compounds of Formula I.

[0126] The conversion of indoles to indolines is well known in the art and can be carried
out as shown or by the methods described in
Somei, M.; Saida, Y.; Funamoto, T.; Ohta, T. Chem. Pharm. Bull. 1987, 35(8), 3146-54;
M. Iwao et. Al. Heterocycles 1992, 34(5), 1031; and
Akagi, M.; Ozaki, K. Heterocycles 1987, 26(1), 61-4.

[0127] The preparation of azaindole oxoacetyl or oxo piperidines with carboxylic acids can
be carried out from nitrile, aldehyde, or anion precursors via hydrolysis, oxidation,
or trapping with CO
2 respectively. As shown in the Scheme 22, Step 1, or the scheme below step a12 one
method for forming the nitrile intermediate, 62, is by cyanide displacement of a halide
in the aza-indole ring. The cyanide reagent used can be sodium cyanide, or more preferably
copper or zinc cyanide. The reactions may be carried out in numerous solvents which
are well known in the art. For example DMF is used in the case of copper cyanide.
Additional procedures useful for carrying out step 1 of Scheme 24 are
Yamaguchi, S.; Yoshida, M.; Miyajima, I.; Araki, T.; Hirai, Y.; J Heterocycl. Chem.
1995, 32(5), 1517-1519 which describes methods for copper cyanide;
Yutilov, Y.M.; Svertilova, I.A.; Khim Geterotsikl Soedin 1994, 8, 1071-1075 which utilizes potassium cyanide; and
Prager, R.H.; Tsopelas, C.; Heisler, T.; Aust. J. Chem. 1991, 44 (2), 277-285 which utilizes copper cyanide in the presence of MeOS(O)
2F. The chloride or more preferably a bromide on the azaindole may be displaced by
sodium cyanide in dioxane via the method described in
Synlett. 1998, 3, 243-244. Alternatively, Nickel dibromide, Zinc, and triphenyl phosphine in can be used to
activate aromatic and heteroaryl chlorides to displacement via potassium cyanide in
THF or other suitable solvent by the methods described in Eur. Pat. Appl.,
831083, 1998.
[0128] The conversion of the cyano intermediate, 62, to the carboxylic acid intermediate,
63, is depicted in step 2, Scheme 22 or in step a12, Scheme 23. Many methods for the
conversion of nitriles to acids are well known in the art and may be employed. Suitable
conditions for step 2 of Scheme 22 or the conversion of intermediate 65 to intermediate
66 below employ potassium hydroxide, water, and an aqueous alcohol such as ethanol.
Typically the reaction must be heated at refluxing temperatures for one to 100 h.
Other procedures for hydrolysis include those described in:
Shiotani, S.; Taniguchi, K.; J. Heterocycl. Chem. 1997, 34(2), 493-499; Boogaard; A. T.; Pandit, U. K.; Koomen, G.-J.; Tetrahedron 1994, 50(8), 2551-2560; Rivalle, C.; Bisagni, E.; Heterocycles 1994, 38(2), 391-397; Macor, J.E.; Post, R.; Ryan, K.; J. Heterocycl. Chem. 1992, 29(6), 1465-1467.
[0129] The acid intermediate, 66 (Scheme 23), may then be esterified using conditions well
known in the art. For example, reaction of the acid with diazomethane in an inert
solvent such as ether, dioxane, or THF would give the methyl ester. Intermediate 67
may then be converted to intermediate 68 according to the procedure described in Scheme
2. Intermediate 68 may then be hydrolyzed to provide intermediate 69.

[0130] As shown in Scheme 24, step a13 another preparation of the indoleoxoacetylpiperazine
7-carboxylic acids, 69, is carried out by oxidation of the corresponding 7-carboxaldehyde,
70. Numerous oxidants are suitable for the conversion of aldehyde to acid and many
of these are described in standard organic chemistry texts such as:
Larock, Richard C., Comprehensive organic transformations : a guide to functional
group preparations 2nd ed. New York : Wiley-VCH, 1999. One preferred method is the use of silver nitrate or silver oxide in a solvent such
as aqueous or anhydrous methanol at a temperature of ~25 °C or as high as reflux.
The reaction is typically carried out for one to 48 h and is typically monitored by
TLC or LC/MS until complete conversion of product to starting material has occurred.
Alternatively, KmnO
4 or CrO
3/H
2SO
4 could be utilized.

[0131] Scheme 25 gives a specific example of the oxidation of an aldehyde intermediate,
70a, to provide the carboxylic acid intermediate, 69a.

[0132] Alternatively, intermediate 69 can be prepared by the nitrile method of synthesis
carried out in an alternative order as shown in Scheme 26. The nitrile hydrolyis step
can be delayed and the nitrile carried through the synthesis to provide a nitrile
which can be hydrolyzed to provide the free acid, 69, as above.

[0133] Step H The direct conversion of nitriles, such as 72, to amides, such as 73, shown in Scheme
27, Step H, can be carried out using the conditions as described in
Shiotani, S.; Taniguchi, K.; J. Heterocycl. Chem. 1996, 33(4), 1051-1056 (describes the use of aqueous sulfuric acid);
Memoli, K.A.; Tetrahedron Lett. 1996, 37(21), 3617-3618;
Adolfsson, H.; Waemmark, K.; Moberg, C.; J. Org. Chem. 1994, 59(8), 2004-2009; and
El Hadri, A.; Leclerc, G.; J. Heterocycl. Chem. 1993, 30(3), 631-635.
Step I For NH2
[0134] Shiotani, S.; Taniguchi, K.; J. Heterocycl. Chem. 1997, 34(2), 493-499;
Boogaard, A. T.; Pandit, U. K.; Koomen, G.-J.; Tetrahedron 1994, 50(8), 2551-2560;
Rivalle, C.; Bisagni, E.; Heterocycles 1994, 38(2), 391-397;
Macor, J.E.; Post, R.; Ryan, K.; J. Heterocycl. Chem. 1992, 29(6), 1465-1467.
Step J
[0135]

[0136] The following scheme (28A) shows an example for the preparation of 4-fluoro-7substituted
azaindoles from a known starting materials. References for the Bartoli indole synthesis
were mentioned earlier. The conditions for tranformation to the nitriles, acids, aldeheydes,
heterocycles and amides have also been described in this application.

[0137] Steps a16, a17, and a18 encompasses reactions and conditions for 1°, 2° and 3° amide
bond formation as shown in Schemes 28 and 29 which provide compounds such as those
of Formula 73.
[0138] The reaction conditions for the formation of amide bonds encompass any reagents that
generate a reactive intermediate for activation of the carboxylic acid to amide formation,
for example (but not limited to), acyl halide, from carbodiimide, acyl iminium salt,
symmetrical anhydrides, mixed anhydrides (including phosphonic/phosphinic mixed anhydrides),
active esters (including silyl ester, methyl ester and thioester), acyl carbonate,
acyl azide, acyl sulfonate and acyloxy N-phosphonium salt. The reaction of the indole
carboxylic acids with amines to form amides may be mediated by standard amide bond
forming conditions described in the art. Some examples for amide bond formation are
listed in references 41-53 but this list is not limiting. Some carboxylic acid to
amine coupling reagents which are applicable are EDC, Diisopropylcarbodiimide or other
carbodiimides, PyBop (benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate),
2-(1H-benzotriazole-1-yl)-1, 1, 3, 3-tetramethyl uronium hexafluorophosphate (HBTU).
A particularly useful method for azaindole 7-carboxylic acid to amide reactions is
the use of carbonyl imidazole as the coupling reagent as described in reference 53.
The temperature of this reaction may be lower than in the cited reference , from 80
°C (or possibly lower) to 150°C or higher. A more specific application is depicted
in Scheme 30.

[0139] The following four general methods provide a more detailed description for the preparation
of indolecarboamides and these methods were employed for the synthesis of compounds
of Formula I.
Method 1:
[0140] To a mixture of an acid intermediate, such as 69, (1 equiv., 0.48 mmol), an appropriate
amine (4 equiv.) and DMAP (58 mg, 0.47 mmol) dissolved CH
2Cl
2 (1 mL) was added EDC (90 mg, 0.47 mmol). The resulting mixture was shaken at rt for
12h, and then evaporated
in vacuo. The residue was dissolved in MeOH, and subjected to preparative reverse phase HPLC
purification.
Method 2:
[0141] To a mixture of an appropriate amine (4 equiv.) and HOBT (16 mg, 0.12 mmol) in THF
(0.5 mL) was added an acid intermediate, such as 69, (25 mg, 0.06 mmol) and NMM (50
µl, 0.45 mmol), followed by EDC (23 mg, 0.12 mmol). The reaction mixture was shaken
at rt for 12 h. The volatiles were evaporated
in vacuo; and the residue dissolved in MeOH and subjected to preparative reverse phase HPLC
purification.
Method 3:
[0142] To a mixture of an acid intermediate, such as 69, (0.047 mmol), amine (4 equiv.)
and DEPBT (prepared according to
Li, H.; Jiang, X. Ye, Y.; Fan, C.; Todd, R; Goodman, M. Organic Letters 1999, 1,
91; 21 mg, 0.071 mmol) in DMF (0.5 mL) was added TEA (0.03 mL, 0.22 mmol). The resulting
mixture was shaken at rt for 12 h; and then diluted with MeOH (2 mL) and purified
by preparative reverse phase HPLC.
Method 4:
[0143] A mixture of an acid intermediate, such as 69, (0.047mmol) and 8.5 mg (0.052mmol))
of 1,1-carbonyldiimidazole in anhydrous THF (2 mL) was heated to reflux under nitrogen.
After 2.5h, 0.052 mmol of amine was added and heating continued. After an additional
period of 3~20 h at reflux, the reaction mixture was cooled and concentrated in vacuo.
The residue was purified by chromatography on silica gel to provide a compound of
Formula I
[0144] In addition, the carboxylic acid may be converted to an acid chloride using reagents
such as thionyl chloride (neat or in an inert solvent) or oxalyl chloride in a solvent
such as benzene, toluene, THF, or CH
2Cl
2. The amides may alternatively, be formed by reaction of the acid chloride with an
excess of ammonia, primary, or secondary amine in an inert solvent such as benzene,
toluene, THF, or CH
2Cl
2 or with stoichiometric amounts of amines in the presence of a tertiary amine such
as triethylamine or a base such as pyridine or 2,6-lutidine. Alternatively, the acid
chloride may be reacted with an amine under basic conditions (Usually sodium or potassium
hydroxide) in solvent mixtures containing water and possibly a miscible co solvent
such as dioxane or THF. Scheme 25B depicts a typical preparation of an acid chloride
and derivatization to an amide of Formula I. Additionally, the carboxylic acid may
be converted to an ester preferably a methyl or ethyl ester and then reacted with
an amine. The ester may be formed by reaction with diazomethane or alternatively trimethylsilyl
diazomethane using standard conditions which are well known in the art. References
and procedures for using these or other ester forming reactions can be found in reference
52 or 54.
[0145] Additional references for the formation of amides from acids are:
Norman, M.H.; Navas, F. III; Thompson, J.B.; Rigdon, G.C.; J. Med Chem. 1996, 39(24),
4692-4703;
Hong, F.; Pang, Y.-P.; Cusack, B.; Richelson, E.; J. Chem. Soc., Perkin Trans 1 1997,
14, 2083-2088;
Langry, K.C.; Org. Prep. Proc. Int. 1994, 26(4), 429-438;
Romero, D.L.; Morge, R.A.; Biles, C.; Berrios-Pena, N.; May, P.D.; Palmer, J.R; Johnson,
P.D.; Smith, H.W.; Busso, M.; Tan, C.-K.; Voorman, R.L.; Reusser, F.; Althaus, I.W.;
Downey, K.M.; et al.; J. Med. Chem. 1994, 37(7), 999-1014;
Bhattacharjee, A.; Mukhopadhyay, R.; Bhattacharjya, A.; Indian J. Chem., Sect B 1994,
33(7), 679-682.

[0147] Yutilov, Y.M.; Svertilova, I. A.; Khim Geterotsikl Soedin 1994, 8, 1071-1075; and
Prager, RH.; Tsopelas, C.; Heisler, T.; Aust. J. Chem. 1991, 44(2), 277-285. Step F-2 of Scheme 31 may be accomplished according to the procedures set forth
in:
Ciurla, H.; Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371;
Robinson, R.P.; Donahue, K.M.; Son, P.S.; Wagy, S.D.; J. Heterocycl. Chem. 1996, 33(2),
287-293;
Nicolai, E.; Claude, S.; Teulon, J. M.; J. Heterocycl. Chem. 1994, 31(1), 73-75;
Hwu, J.R; Wong, F.F.; Shiao, M.-J.; J. Org. Chem. 1992, 57(19), 5254-5255;
Shiao, M.-J.; Lai, L.-L.; Ku, W.-S.; Lin, P.-Y.; Hwu, J.R.; J. Org. Chem. 1993, 58(17),
4742-4744.
[0148] The introduction of an alkoxy or aryloxy substituent onto the azaindole (Step G,
Scheme 31, R
2 is alkoxy or aryloxy) may be accomplished by the f procedures described in
Klemm, L.H.; Zell, R.; J. Heterocycl. Chem. 1968, 5, 773;
Bradsher, C. K.; Brown, F. C.; Porter, H. K.; J. Am. Chem. Soc. 1954, 76, 2357; and
Hodgson, H. H.; Foster, C. K.; J. Chem. Soc. 1942, 581.
[0149] The introduction of a fluorine substituent onto the azaindole (Step G, Scheme 31)
may be accomplished according to the procedures as described in
Sanchez, J. P.; Gogliotti, R. D.; J. Heterocycl. Chem. 1993, 30(4), 855-859;
Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett. 1993, 34(18),
2937-2940; and
Sanchez, J.P.; Rogowski, J.W.; J. Heterocycl. Chem. 1987, 24, 215.
[0150] The introduction of a chlorine substituent onto the azaindole (Step G, Scheme 31)
may be accomplished according to the procedures as described in
Ciurla, H.; Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371;
Raveglia, L.F.; Giardinal, G.A.M.; Grugni, M.; Rigolio, R.; Farina, C.; J. Heterocycl.
Chem. 1997, 34(2), 557-559;
Matsumoto, J.I.; Miyamoto, T.; Minamida, A.; Mishimura, Y.; Egawa, H.; Mishimura,
H.; J. Med. Chem. 1984, 27(3), 292;
Lee, T.-C.; Salemnick, G.; J. Org. Chem. 1975, 24, 3608.
[0151] The introduction of a bromine substituent onto the azaindole (Step G, Scheme 31)
may be accomplished according to the procedures as described in
Raveglia, L.F.; Giardina, G.A.M.; Grugni, M.; Rigolio, R.; Farina, C. ; J. Heterocycl.
Chem. 1997, 34(2), 557-559;
Talik, T.; Talik, Z.; Ban-Oganowska, H.; Synthesis 1974, 293;
Abramovitch, R. A.; Saha, M.; Can. J. Chem. 1966, 44,1765.
[0152] It is well known in the art that heterocycles may be prepared from an aldehyde, carboxylic
acid, carboxylic acid ester, carboxylic acid amide, carboxylic acid halide, or cyano
moiety or attached to another carbon substituted by a bromide or other leaving group
such as a triflate, mesylate, chloride, iodide, or phosponate. The methods for preparing
such intermediates from intermediates typified by the carboxylic acid intermediate,
69, bromo intermediate, 76, or aldehyde intermediate, 70 described above are known
by a typical chemist practitioner. The methods or types of heterocycles which may
be constructed are described in the chemical literature. Some representative references
for finding such heterocycles and their construction are included in reference 55
through 67 but should in no way be construed as limiting. However, examination of
these references shows that many versatile methods are available for synthesizing
diversely substituted heterocycles and it is apparent to one skilled in the art that
these can be applied to prepare compounds of Formula I. Chemists well versed in the
art can now easily, quickly, and routinely find numerous reactions for preparing heterocycles,
amides, oximes or other substituents from the above mentioned starting materials by
searching for reactions or preparations using a conventional electronic database such
as Scifinder (American Chemical Society), Crossfire (Beilstein), Theilheimer, or Reaccs
(MDS). The reaction conditions identified by such a search can then be employed using
the substrates described in this application to produce all of the compounds envisioned
and covered by this invention. In the case of amides, commercially available amines
can be used in the synthesis. Alternatively, the above mentioned search programs can
be used to locate literature preparations of known amines or procedures to synthesize
new amines. These procedures are then carried out by one with typical skill in the
art to provide the compounds of Formula I for use as antiviral agents.
[0153] As shown below in Scheme 32, step a13, suitable substituted azaindoles, such as the
bromoazaindole intermediate, 76, may undergo metal mediated couplings with aryl groups,
heterocycles, or vinyl stannanes to provide compounds of Formula I wherein R
5 is aryl, heteroaryl, or heteroalicyclic for example. The bromoazaindole intermediates,
76 (or azaindole triflates or iodides) may undergo Stille-type coupling with heteroarylstannanes
as shown in Scheme 32, step a13. Conditions for this reaction are well known in the
art and references 68-70 as well as reference 52 provide numerous conditions in addition
to the specific examples provided in Scheme 14 and in the specific embodiments. It
can be well recognized that an indole stannane could also couple to a heterocyclic
or aryl halide or triflate to construct compounds of Formula I. Suzuki coupling (reference
71) between the bromo intermediate, 76, and a suitable boronate could also be employed
and some specific examples are contained in this application.

[0154] As shown in Scheme 34, step a14, aldehyde intermediates, 70, may be used to generate
numerous compounds of Formula I. The aldehyde group may be a precursor for any of
the substituents R
1 through R
5 but the transormation for R
5 is depicted above for simplicity. The aldehyde intermediate 70, may be reacted to
become incorporated into a ring as

described in the claims or be converted into an acyclic group. The aldehyde, 70, may
be reacted with a Tosmic based reagent to generate oxazoles (references 42 and 43
for example). The aldehyde, 70, may be reacted with a Tosmic reagent and than an amine
to give imidazoles as in reference 72 or the aldehyde intermediate, 70, may be reacted
with hydroxylamine to give an oxime which is a compound of Formula I as described
below. Oxidation of the oxime with NBS, t-butyl hypochlorite, or the other known reagents
would provide the N-oxide which react with alkynes or 3 alkoxy vinyl esters to give
isoxazoles of varying substitution. Reaction of the aldehyde intermediate 70, with
the known reagent, 77 (reference 70) shown below under basic conditions would provide
4-aminotrityl oxazoles.

[0155] Removal of the trityl group would provide 4-amino oxazoles which could be substitutued
by acylation, reductive alkylation or alkylation reactions or heterocycle forming
reactions. The trityl could be replaced with an alternate protecting group such as
a monomethoxy trityl, CBZ, benzyl, or appropriate silyl group if desired. Reference
73 demonstrates the preparation of oxazoles containing a triflouoromethyl moiety and
the conditions described therein demonstrates the synthesis of oxazoles with fluorinated
methyl groups appended to them.
[0156] The aldehyde could also be reacted with a metal or Grignard (alkyl, aryl, or heteroaryl)
to generate secondary alcohols. These would be efficacious or could be oxidized to
the ketone with TPAP or MnO
2 or PCC for example to provide ketones of Formula I which could be utilized for treatment
or reacted with metal reagents to give tertiary alcohols or alternatively converted
to oximes by reaction with hydroxylamine hydrochlorides in ethanolic solvents. Alternatively
the aldehyde could be converted to benzyl amines via reductive amination. An example
of oxazole formation via a Tosmic reagent is shown below in Scheme 35. The same reaction
would work with aldehydes at other positions and also in the 5 and 6 aza indole series.

[0157] Scheme 36 shows in step a15, a cyano intermediate, such as 62, which could be directly
converted to compounds of Formula I via heterocycle formation or reaction with organometallic
reagents.

[0158] Scheme 37 shows a method for acylation of a cyanoindole intermediate of formula 65
with oxalyl chloride which would give acid chloride, 79, which could then be coupled
with the appropriate amine in the presence of base to provide 80.

[0159] The nitrile intermediate, 80, could be converted to the tetrazole of formula 81,
which could then be alkylated with trimethylsilyldiazomethane to give the compound
of formula 82 (Scheme 38).

[0160] Tetrazole alkylation with alkyl halides would be carried out prior to azaindole acylation
as shown in Scheme 39. Intermediate 65 could be converted to tetrazole, 83, which
could be alkylated to provide 84. Intermediate 84 could then be acylated and hydrolyzed
to provide 85 which could be subjected to amide formation conditions to provide 86.
The group appended to the tetrazole may be quite diverse and still exhibit impressive
potency.

[0161] Scheme 40 shows that an oxadiazole such as , 88, may be prepared by the addition
of hydroxylamine to the nitrile, 80, followed by ring closure of intermediate 87 with
phosgene. Alkylation of oxadiazole, 88, with trimethylsilyldiazomethane would give
the compound of formula 89.

[0162] A 7-cyanoindole, such as 80, could be efficiently converted to the imidate ester
under conventional Pinner conditions using 1,4-dioxane as the solvent. The imidate
ester can be reacted with nitrogen, oxygen and sulfur nucleophiles to provide C7-substituted
indoles, for example: imidazolines, benzimidazoles, azabenzimidazoles, oxazolines,
oxadiazoles, thiazolines, triazoles, pyrimidines and amidines etc. For example the
imidate may be reacted with acetyl hydrazide with heating in a nonparticipating solvent
such as dioxane, THF, or benzene for example. (aqueous base or aqueous base in an
alcoholic solvent may need to be added to effect final dehydrative cyclization in
some cases) to form a methyl triazine. Other hydrazines can be used. Triazines can
also be installed via coupling of stannyl triazines with 4,5,6,or 7-bromo or chloro
azaindoles. The examples give an example of the formation of many of these heterocycles.
References:
[0163]
(1) Das, B. P.; Boykin, D. W. J. Med. Chem. 1977, 20, 531.
(2) Czarny, A.; Wilson, W. D.; Boykin, D. W. J. Heterocyclic Chem. 1996, 33, 1393.
(3) Francesconi, I.; Wilson, W. D.; Tanious, F. A.; Hall, J. E.; Bender, B. C.; Tidwell,
R. R.; McCurdy, D.; Boykin, D. W. J. Med. Chem. 1999, 42, 2260.
[0164] Scheme 41 shows addition of either hydroxylamine or hydroxylamine acetic acid to
aldehyde intermediate 90 may give oximes of Formula 91.

[0165] An acid may be a precursor for substituents R
1 through R
5 when it occupies the corresponding position such as R
5 as shown in Scheme 42.

[0166] An acid intermediate, such as 69, may be used as a versatile precursor to generate
numerous substituted compounds. The acid could be converted to hydrazonyl bromide
and then a pyrazole via reference 74. One method for general heterocycle synthesis
would be to convert the acid to an alpha bromo ketone (ref 75) by conversion to the
acid chloride using standard methods, reaction with diazomethane, and finally reaction
with HBr. The alpha bromo ketone could be used to prepare many different compounds
of Formula I as it can be converted to many heterocycles or other compounds of Formula
I. Alpha amino ketones can be prepared by displacement of the bromide with amines.
Alternatively, the alpha bromo ketone could be used to prepare heterocycles not available
directly from the aldeheyde or acid. For example, using the conditions of Hulton in
reference 76 to react with the alpha bromo ketone would provide oxazoles. Reaction
of the alpha bromoketone with urea via the methods of reference 77 would provide 2-amino
oxazoles. The alpha bromoketone could also be used to generate furans using beta keto
esters(ref 78-80) or other methods, pyrroles (from beta dicarbonyls as in ref 81 or
by Hantsch methods (ref 82) thiazoles , isoxazoles and imidazoles (ref 83) example
using literature procedures. Coupling of the aforementioned acid chloride with N-methyl-O-methyl
hydroxyl amine would provide a "Weinreb Amide" which could be used to react with alkyl
lithiums or Grignard reagents to generate ketones. Reaction of the Weinreb anion with
a dianion of a hydroxyl amine would generate isoxazoles (ref 84). Reaction with an
acetylenic lithium or other carbanion would generate alkynyl indole ketones. Reaction
of this alkynyl intermediate with diazomethane or other diazo compounds would give
pyrazoles (ref 85). Reaction with azide or hydroxyl amine would give heterocycles
after elimination of water. Nitrile oxides would react with the alkynyl ketone to
give isoxazoles (ref 86). Reaction of the initial acid to provide an acid chloride
using for example oxalyl chloride or thionyl chloride or triphenyl phosphine/ carbon
tetrachloride provides a useful intermediate as noted above. Reaction of the acid
chloride with an alpha ester substituted isocyanide and base would give 2-substituted
oxazoles (ref 87). These could be converted to amines, alcohols, or halides using
standard reductions or Hoffman/Curtius type rearrangements.
[0168] Step B'" shows displacement with potassium cyanide would provide the cyano derivative
according to the method described in
Miyashita, K.; Kondoh, K.; Tsuchiya, K.; Miyabe, H.; Imanishi, T.; Chem. Pharm. Bull.
1997, 45(5), 932-935 or in
Kawase, M.; Sinhababu, A.K.; Borchardt, R.T.; Chem. Pharm. Bull. 1990, 38(11), 2939-2946. The same transformation could also be carried out using TMSCN and a tetrabutylammonium
flouride source as in
Iwao, M.; Motoi, O.; Tetrahedron Lett. 1995, 36(33), 5929-5932. Sodium cyanide could also be utilized.

[0169] Step C'" of Scheme 43 depicts hydrolysis of the nitrile with sodium hydroxide and
methanol would provide the acid via the methods described in
Iwao, M.; Motoi, O.; Tetrahedron Lett. 1995, 36(33), 5929-5932 for example. Other basic hydrolysis conditions using either NaOH or KOH as described
in
Thesing, J.; et al.; Chem. Ber. 1955, 88, 1295 and
Geissman, T.A.; Armen, A.; J. Am. Chem. Soc. 1952, 74, 3916. The use of a nitrilase enzyme to achieve the same transformation is described by
Klempier N, de Raadt A, Griengl H, Heinisch G, J. Heterocycl. Chem., 1992 29, 93, and may be applicable.
[0170] Step D"' of Scheme 43 depicts an alpha hydroxylation which may be accomplished by
methods as described in
Hanessian, S.; Wang, W.; Gai, Y.; Tetrahedron Lett. 1996, 37(42), 7477-7480;
Robinson, R. A.; Clark, J. S.; Holmes, A. B.; J. Am. Chem. Soc. 1993, 115(22), 10400-10401 (KN(TMS)
2 and then camphorsulfonyloxaziridine or another oxaziridine; and
Davis, F.A.; Reddy, R.T.; Reddy, R.E.; J. Org. Chem. 1992, 57(24), 6387-6389.
[0171] Step E"' of Scheme 43 shows methods for the oxidation of the alpha hydroxy ester
to the ketone which may be accomplished according to the methods described in
Mohand, S.A.; Levina, A.; Muzart, J.; Synth. Comm. 1995, 25 (14), 2051-2059. A preferred method for step E'" is that of
Ma, Z.; Bobbitt, J.M.; J. Org. Chem. 1991, 56(21), 6110-6114 which utilizes 4-(NH-Ac)-TEMPO in a solvent such as CH
2Cl
2 in the presence of para toluenesulfonic acid. The method described in
Corson, B.B.; Dodge, R.A.; Harris, S.A.; Hazen, R.K.; Org. Synth. 1941, I, 241 for the oxidation of the alpha hydroxy ester to the ketone uses KmnO
4 as oxidant. Other methods for the oxidation of the alpha hydroxy ester to the ketone
include those described in
Hunaeus, ; Zincke,; Ber. Dtsch Chem. Ges. 1877, 10, 1489;
Acree,; Am. Chem. 1913, 50, 391; and
Claisen,; Ber. Dtsch. Chem. Ges. 1877, 10, 846.
[0172] Step F"' of Scheme 43 depicts the coupling reactions which may be carried out as
described previously in the application and by a preferred method which is described
in
Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M. Organic Lett., 1999,
1, 91-93 and employs 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3
H)-one (DEPBT); a new coupling reagent with remarkable resistance to racemization.

[0173] Scheme 44 depicts the preparation of Formula I compounds by coupling HWC(O)A to the
acid as described in Step F"' of Scheme 43, followed by hydroxylation as in Step D"'
of Scheme 43 and oxidation as described in Step E'" of Scheme 43.

[0174] Scheme 45 depicts a method for the preparation which could be used to obtain amido
compounds of Formula I. Step G' represents ester hydrolysis followed by amide formation
(Step H' as described in Step F"' of Scheme 43). Step I' of Scheme 45 depicts the
preparation of the N-oxide which could be accomplished according to the procedures
in
Suzuki, H.; Iwata, C.; Sakurai, K.; Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama,
Y.; Murakami, Y.; Tetrahedron 1997, 53(5), 1593-1606;
Suzuki, H.; Yokoyama, Y.; Miyagi, C.; Murakami, Y.; Chem. Pharm. Bull. 1991, 39(8),
2170-2172; and
Ohmato, T.; Koike, K.; Sakamoto, Y.; Chem. Pharm. Bull. 1981, 29, 390. Cyanation of the N-oxide is shown in Step J' of Scheme 45 which may be accomplished
according to
Suzuki, H.; Iwata, C.; Sakurai, K.; Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama,
Y.; Murakami, Y.; Tetrahedron 1997, 53(5), 1593-1606 and
Suzuki, H.; Yokoyama, Y.; Miyagi, C.; Murakami, Y.; Chem. Pharm. Bull. 1991, 39(8),
2170-2172. Hydrolysis of the nitrile to the acid is depicted in Step K' of Scheme 45 according
to procedures such as
Shiotani, S.; Tanigucchi, K.; J. Heterocycl. Chem. 1996, 33(4), 1051-1056;
Memoli, K.A.; Tetrahedron Lett. 1996, 37(21), 3617-3618;
Adolfsson, H.; Waemmark, K.; Moberg, C.; J. Org. Chem. 1994, 59(8), 2004-2009; and
El Hadri, A.; Leclerc, G.; J. Heterocycl. Chem. 1993, 30(3), 631-635. Step L' of Scheme 45 depicts a method which could be utilized for the preparation
of amido compounds of Formula I from the cyano derivative which may be accomplished
according to procedures described in
Shiotani, S.; Taniguchi, K.; J. Heterocycl. Chem. 1997, 34(2), 493-499;
Boogaard, A.T.; Pandit, U.K.; Koomen, G.-J.; Tetrahedron 1994, 50(8), 2551-2560;
Rivalle, C.; Bisagni, E.; Heterocycles 1994, 38(2), 391-397; and
Macor, J.E.; Post, R.; Ryan, K.; J. Heterocycl. Chem. 1992, 29(6), 1465-1467. Step M' of Scheme 45 shows a method which could be used for the preparation of amido
compounds of Formula I from the acid derivative which may be accomplished according
to procedures described in
Norman, M.H.; Navas, F. III; Thompson, J.B.; Rigdon, G.C.; J. Med Chem. 1996, 39(24),
4692-4703;
Hong, F.; Pang, Y.-P.; Cusack, B.; Richelson, E.; J. Chem. Soc., Perkin Trans 1 1997,
14, 2083-2088;
Langry, K. C.; Org. Prep. Proced. Int. 1994, 26(4), 429-438;
Romero, D.L.; Morge, R.A.; Biles, C.; Berrios-Pena, N.; May, P.D.; Palmer, J.R.; Johnson,
P.D.; Smith, H.W.; Busso, M.; Tan, C.-K.; Voorman, R.L.; Reusser, F.; Althaus, I.W.;
Downey, K.M.; et al.; J. Med. Chem. 1994, 37(7), 999-1014 and
Bhattacharjee, A.; Mukhopadhyay, R.; Bhattacharjya, A.; Indian J. Chem., Sect B 1994,
33(7), 679-682.

[0175] Scheme 46 shows a method which could be used for the synthesis of an azaindole acetic
acid derivative. Protection of the amine group could be effected by treatment with
di-tert-butyldicarbonate to introduce the t-Butoxycarbonyl (BOC) group. Introduction
of the oxalate moiety may then be accomplished as shown in Step A of Scheme 46 according
to the procedures described in
Hewawasam, P.; Meanwell, N. A.; Tetrahedron Lett. 1994, 35(40), 7303-7306 (using t-Buli, or s-buli, THF); or
Stanetty, P.; Koller, H.; Mihovilovic, M.; J. Org. Chem. 1992, 57(25), 6833-6837 (using t-Buli). The intermediate thus formed could then be cyclized to form the azaindole
as shown in Step B of Scheme 46 according to the procedures described in
Fuerstner, A.; Ernst, A.; Krause, H.; Ptock, A.; Tetrahedron 1996, 52(21), 7329-7344 (using. TiCl3, Zn, DME); or
Fuerstner, A.; Hupperts, A.; J. Am. Chem. Soc. 1995, 117(16), 4468-4475 (using Zn, excess Tms-Cl, TiCl3 (cat.), MeCN).

[0176] Scheme 47 describes an alternate synthesis which could be used to prepare azaindole
acetic acid derivatives. Step C of Scheme 47 could be accomplished by using the procedures
described in
Harden, F.A.; Quinn, RJ.; Scammells, P.J.; J. Med. Chem. 1991, 34(9), 2892-2898 [use of 1. NaNO
2, conc. HCl 2. SnCl
2, conc. HCl (cat.)]. Typically, 10 equivalents of NaNO
2 and 1.0 equivalents of substrate reacted at 0 °C for 0.25 to 1h and to this reaction
mixture was added 3.5 equivalents of SnCl
2. Alternatively, the procedure described in
De Roos, K.B.; Salemink, C.A.; Recl. Trav. Chim. Pays-Bas 1971, 90, 1181 (use of NaNO
2, AcOH, H
2O) could be used. The intermediate thus formed could be further reacted and cyclized
to provide azaindole acetic acid derivatives as shown in Step D of Scheme 47 and according
to the procedures described in
Atkinson, C. M.; Mattocks, A. R.; J. Chem. Soc. 1957, 3722;
Ain Khan, M.; Ferreira Da Rocha, J.; Heterocycles 1978, 9, 1617;
Fusco, R.; Sannicolo, F.; Tetrahedron 1980, 36, 161 [use of HCl (conc)];
Abramovitch, R. A.; Spenser, I. D.; Adv. Heterocycl. Chem. 1964, 3, 79 (use of ZnCl
2, p-Cymene); and
Clemo, G. R.; Holt, R. J. W.; J. Chem. Soc. 1953, 1313; (use of ZnCl
2, EtOH, Sealed tube).

[0177] Scheme 48 depicts another possible route to azaindole acetic acid derivatives. Step
E of Scheme 48 could be carried out as shown or according to procedures such as those
described in
Yurovskaya, M.A.; Khamlova, I.G.; Nesterov, V.N.; Shishkin, O.V.; Struchkov, T.; Khim
Geterotsikl Soedin 1995, 11, 1543-1550;
Grzegozek, M.; Wozniak, M.; Baranski, A.; Van Der Plas, H.C.; J. Heterocycl. Chem.
1991, 28(4), 1075-1077 (use of NaOH, DMSO);
Lawrence, N.J.; Liddle, J.; Jackson, D.A.; Tetrahedron Lett. 1995, 36(46), 8477-8480 (use of. NaH, DMSO);
Haglund, O.; Nilsson, M.; Synthesis 1994, 3, 242-244; (use of 2.5 equiv. CuCl, 3.5 equiv. TBu-OK, DME, Py);
Makosza, M.; Sienkiewicz, K.; Wojciechowski, K.; Synthesis 1990, 9, 850-852; (use of KO-tBu, DMF);
Makosza, M.; Nizamov, S.; Org. Prep. Proceed Int. 1997, 29(6), 707-710; (use of tBu-OK, THF). Step F of Scheme 48 shows the cyclization reaction which could
provide the azaindole acetic acid derivatives. This reaction could be accomplished
according to procedures such as those described in
Frydman, B.; Baldain, G.; Repetto, J. C.; J. Org. Chem. 1973, 38, 1824 (use of H
2, Pd-C, EtOH);
Bistryakova, I. D.; Smimova, N. M.; Safonova, T. S.; Khim Geterotsikl Soedin 1993,
6, 800-803 (use of H
2, Pd-C (cat.), MeOH);
Taga, M.; Ohtsuka, H.; Inoue, I.; Kawaguchi, T.; Nomura, S.; Yamada, K.; Date, T.;
Hiramatsu, H.; Sato, Y.; Heterocycles 1996, 42(1), 251-263 (use of SnCl
2, HCl, Et
2O);
Arcari, M.; Aveta, R.; Brandt, A.; Cecchetelli, L.; Corsi, G.B.; Dirella, M.; Gazz.
Chim. Ital. 1991,121 (11), 499-504 [use of Na
2S
2O
6, THF/EtOH/H
2O (2:2:1)];
Moody, C. J.; Rahimtoola, K. F.; J. Chem. Soc., Perkin Trans 1 1990, 673 (use of TiCl
3, NH
4Oac, acetone, H
2O).
[0179] Scheme 50 shows the preparation of azaindole oxalic acid derivatives. The starting
materials in Scheme 50 may be prepared according to
Tetrahedron Lett. 1995, 36, 2389-2392. Steps A', B', C', and D' of Scheme 50 may be carried out according to procedures
described in
Jones, R.A.; Pastor, J.; Siro, J.; Voro, T.N.; Tetrahedron 1997, 53(2), 479-486; and
Singh, S.K.; Dekhane, M.; Le Hyaric, M.; Potier, P.; Dodd, R.H.; Heterocycles 1997,
44(1), 379-391. Step E' of Scheme 50 could be carried out according to the procedures described
in
Suzuki, H.; Iwata, C.; Sakurai, K.; Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama,
Y.; Murakami, Y.; Tetrahedron 1997, 53(5), 1593-1606;
Suzuki, H.; Yokoyama, Y.; Miyagi, C.; Murakami, Y.; Chem. Pharm. Bull. 1991, 39(8),
2170-2172;
Hagen, T.J.; Narayanan, K.; Names, J.; Cook, J.M.; J. Org. Chem. 1989, 54, 2170;
Murakami, Y.; Yokoyama, Y.; Watanabe, T.; Aoki, C.; et al.; Heterocycles 1987, 26,
875; and
Hagen, T. J.; Cook, J.M.; Tetrahedron Lett. 1988, 29(20), 2421. Step F' of Scheme 50 shows the conversion of the phenol to a fluoro, chloro or bromo
derivative. Conversion of the phenol to the fluoro derivative could be carried out
according to procedures described in
Christe, K.O.; Pavlath, A.E.; J. Org. Chem. 1965, 30, 3170;
Murakami, Y.; Aoyama, Y.; Nakanishi, S.; Chem. Lett. 1976, 857;
Christe, K. O.; Pavlath, A. E.; J. Org. Chem. 1965, 30, 4104; and
Christe, K.O.; Pavlath, A.E.; J. Org. Chem. 1966, 31, 559. Conversion of the phenol to the chloro derivative could be carried out according
to procedures described in
Wright, S.W.; Org. Prep. Proc. Int. 1997, 29(1), 128-131;
Hartmann, H.; Schulze, M.; Guenther, R.; Dyes Pigm 1991, 16(2), 119-136;
Bay, E.; Bak, D. A.; Timony, P. E.; Leone-Bay, A.; J. Org. Chem. 1990, 55, 3415;
Hoffmann, H.; et al.; Chem. Ber. 1962, 95, 523; and
Vanallan, J.A.; Reynolds, G.A.; J. Org. Chem. 1963, 28, 1022. Conversion of the phenol to the bromo derivative may be carried out according to
procedures described in
Katritzky, A.R.; Li, J.; Stevens, C.V.; Ager, D.J.; Org. Prep. Proc. Int. 1994, 26(4),
439-444;
Judice, J.K.; Keipert, S.J.; Cram, D.J.; J. Chem. Soc., Chem. Commun. 1993, 17, 1323-1325;
Schaeffer, J.P.; Higgins, J.; J. Org. Chem. 1967, 32, 1607;
Wiley, G.A.; Hershkowitz, R.L.; Rein, R.M.; Chung, B.C.; J. Am. Chem. Soc. 1964, 86,
964; and
Tayaka, H.; Akutagawa, S.; Noyori, R.; Org. Syn. 1988, 67, 20.

[0180] Scheme 51 describes methods for the preparation of azaindole acetic acid derivatives
by the same methods employed for the preparation of azaindole oxalic acid derivatives
as shown and described in Scheme 50 above. The starting material employed in Scheme
51 could be prepared according to
J. Org. Chem. 1999, 64, 7788-7801. Steps A", B", C", D", and E" of Scheme 51 could be carried out in the same fashion
as previously described for Steps Steps A', B', C', D', and E' of Scheme 50.

[0181] The remaining schemes provide additional background, examples, and conditions for
carrying out this invention. Specific methods for preparing W and modifying A are
presented. As shown in Scheme 52, the azaindoles may be treated with oxalyl chloride
in either THF or ether to afford the desired glyoxyl chlorides according to literature
procedures (
Lingens, F.; Lange, J. Justus Liebigs Ann. Chem. 1970, 738, 46-53). The intermediate glyoxyl chlorides may be coupled with benzoyl piperazines (
Desai, M.; Watthey, J.W. Org. Prep. Proc. Int. 1976, 8, 85-86) under basic conditions to afford compounds of Formula I directly.

[0182] Alternatively,
Scheme 52 treatment of the azaindole-3-glyoxyl chloride, (Scheme 52) with tert-butyl 1-piperazinecarboxylate
affords the piperazine coupled product. It is apparent to one skilled in the art that
use of an alternative Boc protected piperazine which are synthesized as shown below
would provide compounds of formula I with alternative groups of formula W. As discussed
earlier, other amine protecting groups which do not require acidic deprotection conditions
could be utilized if desired. Deprotection of the Boc group is effected with 20% TFA/CH
2Cl
2 to yield the free piperazine. This product is then coupled with carboxylic acid in
the presence of polymer supported 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (P-EDC)
to afford products of Formula I. This sequence provides a general method for synthesizing
compounds of varied A in formula I.

[0183] An example for preparing compounds of Formula I which possess substituents in A (or
other parts of the molecule) which might interfere with the standard reaction schemes
reactions is shown in Scheme 53. The piperazine derivative (Scheme 53) was treated
with Boc-protected aminobenzoic acid in the presence of EDC to afford the piperazine
diamide. A portion of the resulting product was separated and subjected to TFA in
order to remove the Boc group, thus yielding amino derivatives.

[0184] Similarly, substituents which possess a reactive alcohol can be incorporated as.
below. The piperazine derivative (Scheme 54) was treated with acetoxybenzoic acid
in the presence of EDC to afford the piperazine diamide derivative. A portion of the
resulting product was separated and subjected to LiOH hydrolysis in order to remove
the acetate group, thus yielding hydroxy derivatives.
[0185] Examples containing substituted piperazines are prepared using the general procedures
outlined in Schemes 55-38. Substituted piperazines are either commercially available
from Aldrich, Co. or prepared according to literature procedures (Behun et al, Ref.
88(a), Scheme 3.1, eq. 01). Hydrogenation of alkyl substituted pyrazines under 40
to 50 psi pressure in EtOH afforded substituted piperazines. When the substituent
was an ester or amide, the pyrazine systems could be partially reduced to the tetrahydropyrazine
(Rossen et al, Ref. 88(b), Scheme 55, eq. 02). The carbonyl substituted piperazines
could be obtained under the same conditions described above by using commercially
available dibenzyl piperazines (Scheme 55, eq. 03).

[0186] 2-Trifluoromethylpiperazine (Jenneskens et al., Ref. 88c) was prepared through a
four step route (Scheme 56). Using Lewis acid TiCl
4, N,N'-dibenzylethylenediamine reacted with trifluoropyruvates to afford the hemiacetal,
which was reduced at room temperature by Et
3SiH in TFA to afford the lactam. LiAlH
4 treatment then reduced the lactam to 1,4-dibenzyl-2-trifluoromethylpiperazine. Finally,
hydrogenation of the dibenzyl-2-trifluoromethylpiperazine in HOAc gave the desired
product, 2-trifluoromethylpiperazine.

[0187] Mono-benzoylation of symmetric substituted piperazines could be achieved by using
one of the following procedures (Scheme 57). (a) Treatment of a solution of piperazine
in acetic acid with acetyl chloride afforded the desired mon-benzoylated piperazine
(Desai et al. Ref. 27, Scheme 57, eq. 04). (b) Symmetric piperazines were treated
with 2 equivalents of n-butyllithium, followed by the addition of benzoyl chloride
at room temperature (Wang et al, Ref. 89, Scheme 57, eq. 05).

[0188] Mono-benzoylation of unsymmetric substituted piperazines could be achieved by using
one of the following procedures (Scheme 57), in which all the methods were exemplified
by mono-alkyl substituted piperazines. (a) Unsymmetric piperazines were treated with
2 equivalents of n-butyllithium, followed by the addition of benzoyl chloride at room
temperature to afford a mixture of two regioisomers, which could be separated by chromatography
(Wang et al, Ref. 89 and 90(b), Scheme 58 eq. 06); (b) Benzoic acid was converted
to its pentafluorophenyl ester, and then further reaction with 2-alkylpiperazine to
provide the mono-benzoylpiperazines with the benzoyl group at the less hindered nitrogen
(Adamczyk et al, Ref. 90(a), Scheme 58, eq. 07); (c) A mixture of piperazine and methyl
benzoate was treated with dialkylaluminum chloride in methylene chloride for 2-4 days
to yield the mono-benzoylpiperazine with the benzoyl group at the less hindered nitrogen
(Scheme 58 eq. 08); (d) Unsymmetric piperazines were treated with 2 equivalents of
n-butyllithium, followed by subsequent addition of triethylsilyl chloride and benzoyl
chloride in THF at room temperature to afford mono-benzoylpiperazines with the benzoyl
group at the more hindered nitrogen (Wang et al, Ref. 90(b), Scheme 58, eq. 09). When
the substituent at position 2 was a ester or amide, the mono-benzoylation with benzoyl
chloride occurred at the less hindered nitrogen of the piperazine with triethylamine
as base in THF (Scheme 58, eq. 10).

[0189] In the case of tetrahydropyrazines (Scheme 59, eq. 11), mono-benzoylation occurred
at the more hindered nitrogen under the same conditions as those in equation 10 of
Scheme 58, in the well precedented manner. (Rossen et al, Ref. 88(b)).

[0190] Furthermore, the ester group can be selectively reduced by NaBH
4 in the presence of the benzamide (Masuzawa et al, Ref. 91), which is shown in Scheme
60.

[0191] The ester groups on either the piperazine linkers or on the azaindole nucleus could
be hydrolyzed to the corresponding acid under basic conditions such as K
2CO
3 (Scheme 61, eq. 13) or NaOMe (Scheme 61, eq. 14) as bases in MeOH and water.

[0192] Reaction of an azaindole glyoxyl chloride with substituted benzoyl piperazines or
tetrahydropyrazines in CH
2Cl
2 using I-Pr
2Net as base afforded the coupled products as shown in Scheme 62.

[0193] In the case of coupling reactions using 3-hydroxylmethyl-benzoylpiperazine, the hydroxyl
group was temporarily protected as its TMS ether with BSTFA (N,O-bistrimethylsilyl)triffuoroacetamide)
(Furber et al, Ref. 92). The unprotected nitrogen atom can then be reacted with glyoxyl
chlorides to form the desired diamides. During workup, the TMS masking group was removed
to give free hydroxylmethylpiperazine diamides as shown in Scheme 63.

[0195] Throughout the chemistry discussion, chemical transformations which are well known
in the art have been discussed. The average practioner in the art knows these transformations
well and a comprehensive list of useful conditions for nearly all the transformations
is available to organic chemists and this list is contained in reference 52 authored
by Larock and is incorporated in its entirety for the synthesis of compounds of Formula
I.
Chemistry
General:
[0196] Additional preparations of starting materials and intermediates are contained in
Wang et. al. PCT WO 01/62255 which is incorporated by reference.
Chemistry
[0197] All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10AS liquid chromatograph
using a SPD-10AV UV-Vis detector with Mass Spectrometry (MS) data determined using
a Micromass Platform for LC in electrospray mode.
LC/MS Method (i.e., compound identification)
[0198]
Column A: |
YMC ODS-A S7 3.0x50 mm column |
Column B: |
PHX-LLTNA C18 4.6x30 mm column |
Column C: |
TERRA ms C18 4.6x30 mm column |
Column D: |
YMC ODS-A C18 4.6x30 mm column |
Column E: |
YMC ODS-A C18 4.6x33 mm column |
Column F: |
YMC C18 S5 4.6x50 mm column |
Column G: |
XTERRA C18 S7 3.0x50 mm column |
Gradient: |
100% Solvent A / 0% Solvent B to 0% Solvent A / 100% Solvent B |
Solvent A = 10% MeOH - 90% H
2O - 0.1 % TFA, Solvent B = 90% MeOH - 10% H
2O-0.1% TFA; and R
t in min.
Gradient time: 2 minutes
Hold time |
1 minute |
Flow rate: |
5 mL/min |
Detector Wavelength: |
220 nm |
Solvent A: |
10% MeOH / 90% H2O / 0.1 % Trifluoroacetic Acid |
Solvent B: |
10% H2O / 90% MeOH / 0.1% Trifluoroacetic Acid |
[0199] Compounds purified by preparative HPLC were diluted in MeOH (1.2 mL) and purified
using the following methods on a Shimadzu LC-10A automated preparative HPLC system
or on a Shimadzu LC-8A automated preparative HPLC system with detector (SPD-10AV UV-VIS)
wavelength and solvent systems (A and B) the same as above.
Preparative HPLC Method (i.e., compound purification)
[0200] Purification Method: Initial gradient (40% B, 60% A) ramp to final gradient (100%
B, 0% A) over 20 minutes, hold for 3 minutes (100% B, 0% A)
Solvent A: |
10% MeOH / 90% H2O / 0.1 % Trifluoroacetic Acid |
Solvent B: |
10% H2O / 90% MeOH / 0.1% Trifluoroacetic Acid |
Column: |
YMC C18 S5 20x100 mm column |
Detector Wavelength: |
220 nm |
Typical Procedures and Characterization of Selected Examples:
Preparation of Intermediates:
Intermediate 1
[0201]

[0202] 4-Methoxyphenylboronic acid (24.54 g), 4-chloro-3-nitropyridine hydrochloride (26.24
g), Pd(Ph
3P)
4 (4 g) and K
2CO
3 (111g) were combined in DME (500 mL). The reaction was heated to reflux for 10 hours.
After the mixture cooled down to room temperature, it was poured into saturated aqueous
NH
4OAc (500 mL )solution. The aqueous phase was extracted with EtOAc (3 x 200 mL). The
combined extract was concentrated to give a residue which was purified using silica
gel chromatography (10% to 30% EtOAc / PE) to afford 10.6 g of Intermediate 1, 3-Nitro-4-(4-methoxyphenyl)pyridine.
MS
m/z: (M+H)
+ calcd for C
12H
11N
2O
3: 231.08; found 231.02. HPLC retention time: 1.07 minutes (column B).
Intermediate 1a
Alternate route to 5-azaindoles:
[0203]

2-methoxy-5-bromo pyridine can be purchased from Aldrich (or others) or prepared.
Oxidation with 1.1 eq of MCPBA in dichloromethane (20ml per 10.6 mmol bromide) in
the presence of anhydrous MgSO4 (0.4g per mL dichloromethane) with stirring from 0°
to ambient temperature for approximately 14 h provided the N-oxide after workup and
flash chromatographic purification over silica gel using a 5% Etoac/Hexane gradient
of increasing EtOAc. The N-oxide (1.6g) was dissolved in 10mL 98% sulfuric acid and
cooled to 0°. 10 mL of 69% nitric acid was added and then allowed to warm to ambient
temp with stirring. The reaction was then heated and stirred at 80° C for 14h and
then poured over ice, extracted with dichloromethane, washed with water, and concentrated
to give a yellow solid which was purified by flash chromatography over Silica gel
using 1: EtOAc/hexane and then a gradient to provide a yellow crystalline solid: ).
1H NMR (CDCl3) δ 8.50 (s,1H), 7.59 (s,1H), 4.12 (3H, s). LC MS showed desired M+H.
TheN-oxide was reduced by dissolving the startingmaterial in dichloromethane (0.147M
substrate) and cooling to 0°. A solution of 1.2 eq PCl
3 (0.44M) in dicloromethane was added slowly to keep the reaction at 0°. Warm to ambient
temp and stir for 72h. Aqueous workup and concentration provided a yellow solid which
could be used in subsequent reactions or purified by chromatography. Note: a similar
sequence could be used with 2-methoxy-5-chloro-pyridine as starting material.
Intermediate 2a
[0204]

[0205] Typical procedure for preparing azaindole from nitropyridine: Preparation of 7-chloro-6-azaindole, Intermediate 2a, is an example of Step A of
Scheme 1. 2-chloro-3-nitropyridine (5.0g, 31.5mmol)) was dissolved in dry THF (200
mL). After the solution was cooled to -78 °C, vinyl magnesium bromide (1.0M in THF,
100 mL) was added dropwise. The reaction temperature was maintained at -78°C for 1
h, and then at -20°C for another 12 h before it was quenched by addition of 20% NH
4Cl aqueous solution (150 mL). The aqueous phase was extracted with EtOAc (3 x 150
mL). The combined organic layer was dried over MgSO
4 , filtered and the filtrate was concentrated
in vacuo to give a residue which was purified by silica gel column chromatography (EtOAc /
Hexane, 1 / 10) to afford 1.5g (31%) of 7-chloro-6-azaindole, Intermediate 2a.
1H NMR (500 MHz, CD
3OD) δ 7.84 (d,1H,
J = 10.7 Hz), 7.55 (dd, 1H,
J = 10.9, 5.45 Hz), 6.62 (d, 1H,
J = 5.54 Hz), 4.89 (s, 1H). MS
m/z: (M+H)
+ calcd for C
7H
6ClN
2: 153.02; found 152.93. HPLC retention time: 0.43 minutes (column A).
Intermediate 2b
[0206]

[0207] Intermediate 2b, 7-(4-Methoxyphenyl)-4-azaindole, was prepared by the same method
as Intermediate 2a starting from 3-Nitro-4-(4-methoxyphenyl)pyridine, Intermediate
1. MS m/z: (M+H)
+ calcd for C
14H
13N
2O: 225.10; found 225.02. HPLC retention time: 1.39 minutes (column B).
Intermediate 2c
[0208]

[0209] Intermediate 2c, 4-bromo-7-chloro-6-azaindole, was prepared by the same method as
Intermediate 2a, starting from 2-Chloro-3-nitro-5-bromo-pyridine (available from Aldrich,
Co.). MS m/z: (M+H)
+ calcd for C
7H
5BrCIN
2: 230.93; found 231.15. HPLC retention time: 1.62 minutes (column B).
Intermediate 2d
[0210]

[0211] Intermediate 2d, 4-fluoro-7-chloro-6-azaindole (above), was prepared according to
the following scheme:

[0212] It should be noted that 2-chloro-5-fluoro-3-nitro pyridine, zz3', may be prepared
by the method in example 5B of the reference Marfat, A. ; and Robinson, R. P. ; "Azaoxindole
Derivatives"
US. Patent 5,811,432 1998. The preparation below provides some details which enhance the yields of this route.
[0213] In Step A, compound zz1' (1.2 g, 0.01 mol) was dissolved in sulfuric acid (2.7 mL)
at room temperature. Premixed fuming nitric acid (1 mL) and sulfuric acid was added
dropwise at 5-10 °C to the solution of compound zz1'. The reaction mixture was then
heated at 85 °C for 1 hour, then was cooled to room temperature and poured into ice
(20 g). The yellow solid precipitate was collected by filtration, washed with water
and air dried to provide 1.01 g of compound zz2'.
[0214] In Step B, compound zz2' (500 mg, 3.16 mmol) was dissolved in phosphorous oxychloride
(1.7 mL, 18.9 mmol) and dimethoxyethane at room temperature. The reaction was heated
to 110 °C for 5 hours. The excess phosphorous oxychloride was then removed by concentrating
the reaction mixture in vacuo. The residue was chromatographed on silica gel, eluted
with chloroform (100%) to afford 176 mg of product zz3'.
[0215] In Step C, compound zz3' (140 mg, 0.79 mmol) was dissolved in THF (5 mL) and cooled
to -78 °C under a nitrogen atmosphere. To this solution was added dropwise a solution
of vinyl magnesium bromide (1.2 mmol, 1.0 M in diethyl ether, 1.2 mL). The reaction
mixture was then kept at -20 °C for 15 hours. The reaction mixture was then quenched
with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over magnesium sulfate, filtered, and the filtrate
was concentrated in vacuo. The residue was chromatographed on silica to provide 130
mg of intermediate 2i.
1H NMR (500 MHz, CD
3OD) δ 7.78 (s, 1H), 7.60 (d, 1H,
J = 3.0 Hz), 6.71 (d, 1H,
J = 3.05 Hz). MS
m/
z: (M+H)
+ calcd for C
7H
5CIFN
2: 171.10; found 171.00. HPLC retention time: 1.22 minutes (column A).
[0216] Intermediate 2d, 4-fluoro-7-chloro-6-azaindole, was prepared by the same method as
Intermediate 2a, starting from 2-Chloro-3-nitro-5-fluoro-pyridine which was prepared
according to the procedure above. Experimental details for this preparation are contained
in
Wang et. al. PCT WO 01/62255.
1H NMR (500 MHz, CD
3OD) δ 7.78 (s, 1H), 7.60 (d, 1H,
J = 3.0 Hz), 6.71 (d, 1H,
J = 3.05 Hz). MS
m/
z: (M+H)
+ calcd for C
7HCIFN
2: 171.10; found 171.00. HPLC retention time: 1.22 minutes (column A).
Intermediate 2e
[0217]

[0218] Intermediate 2e was prepared by either Method A or Method B, below:
[0219] Method A: A mixture of 4-bromo-7-chloro-6-azaindole (1 g), CuI (0.65 g) and NaOMe
(4 mL, 25% in methanol) in MeOH (16 mL) was heated at 110 - 120 °C for 16 hours in
a sealed tube. After cooling to room temperature, the reaction mixture was neutralized
with 1N HCl to pH 7. The aqueous solution was extracted with EtOAc (3 x 30 mL). Then
the combined organic layer was dried over MgSO
4, filtered and the filtrate was concentrated
in vacuo to afford a residue, which was purified by using silica gel chromotography to give
0.3 g of 4-methoxy-7-chloro-6-azaindole, Intermediate 2e. MS
m/
z: (M+H)
+ calcd for C
8H
8ClN
2O: 183.03; found 183.09. HPLC retention time: 1.02 minutes (column B).
[0220] Method B :A mixture of 4-bromo-7-chloro-6-azaindole (6 g), CuBr (3.7 g) and NaOMe
(30 mL, 5% in MeOH) was heated at 110°C for 24 hours in a sealed tube. After cooling
to room temperature, the reaction mixture was added to saturated aqueous NH
4Cl. The resulting aqueous solution was extracted with EtOAc (3 x 30 mL). The combined
organic layer was dried over MgSO
4, filtered and the filtrate was concentrated
in vacuo to afford a residue, which was purified by using silica gel chromotography to give
1.8 g of 4-methoxy-7-chloro-6-azaindole, Intermediate 2e.
Intermediate 2f
[0221]

[0222] Intermediate 2f, 7-bromo-6-azaindole was prepared by the same method as Intermediate
2a, starting from 2-Bromo-3-nitro-pyridine (available from Aldrich, Co.). MS m/z:
(M+H)
+ calcd for C
7H
6BrN
2: 197.97; found 197.01. HPLC retention time: 0.50 minutes (column A).
Intermediate 2g
[0223]

[0224] Intermediate 2g, 7-chloro-4-azaindole was prepared by the same method as Intermediate
2a, starting from 4-Chloro-3-nitro-pyridine (HCl salt, available from Austin Chemical
Company, Inc.). MS
m/
z: (M+H)
+ calcd for C
7H
6ClN
2: 153.02; found 152.90. HPLC retention time: 0.45 minutes (column A).
Intermediate 2h
[0225]

[0226] Intermediate 2h, 5-chloro-7-methyl-4-azaindole was prepared by the same method as
Intermediate 2a, starting from 2-Chloro-4-methyl-5-nitro-pyridine (available from
Aldrich, Co.). MS
m/
z: (M+H)
+ calcd for C
8H
8ClN
2: 167.04; found 166.99. HPLC retention time: 1.22 minutes (column B).
Example 2i
[0227]

[0228] Intermediate 2j, 4-fluoro-7-bromo-6-azaindole, was prepared by the same method as
Intermediate 2e, using POBr
3 in the step B instead of POCl
3. MS m/z: (M+H)
+ calcd for C
7H
5BrFN
2: 214.96; found 214.97. HPLC retention time: 1.28 minutes (column G).
Intermediate 2j
[0229]

[0230] To a mixture of 5-bromo-2-chloro-3-nitropyridine (10 g, 42 mmol) in 1,4-dioxane (100
ml) was added pyrazole (5.8 g, 85 mmol). The resulting mixture was stirred at 120°C
for 26.5 h., and then evaporated after cooling to r.t. The crude material was purified
by flash chromatography (0 to 5% EtOAc/Hexanes) to give the desired product 5-Bromo-3-nitro-2-pyrazol-1-yl-pyridine.
1H NMR: (CD
3OD) δ 8.77 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 7.73 (s, 1H), 6.57 (s, 1H);
LC/MS: (ES+) m/z (M+H)
+= 269, 271, HPLC R
t = 1.223.
[0231] To a 250 mL round bottom flask was charged 5-Bromo-3-nitro-2-pyrazol-1-yl-pyridine
(1.02 g, 3.8 mmol) and THF (30 ml). The mixture was then cooled to - 78°C, and added
a THF solution of vinylmagnesium bromide (23 mL, 18.4 mmol, 0.8
M). After three minutes, the reaction mixture was warmed to -45°C and remained stirring
for
1 h. The reaction was then quenched with ammonium chloride, and the resulting mixture
extracted with EtOAc. The combined extracts were evaporated
in vacuo, and the residue purified by flash column chromatography (5% EtOAc/Hexanes) to give
compound
2 (which by HPLC contained about 50% of a side product, presumably 3-vinylamino of
compound
1) ;
1H NMR: (CDCl
3) δ 10.75 (b s, 1H), 8.73 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.52 (s, 1H), 6.67
(s, 1H), 6.53 (s, 1H);
LC/MS: (ES+) m/z (M+H) = 262, 264; HPLC R
t = 1.670.
Intermediate 2k
[0232]

[0233] To a solution of 2-bromo-5-chloro-3-nitropyridine 5 (20 g, 84 mmol, prepared in 2
steps from 2-amino-5-chloropyridine as described in
WO9622990) in THF (300 ml) at -78°C was charged a THF solution of vinylmagnesium bromide (280
ml, 252 mmol, 0.9
M). The resulting mixture was stirred at -78°C for one hour, followed by quenching
with aqueous ammonium chloride (500 ml,
sat.) and extracted with EtOAc (5 x 500 ml). The combined organic extracts were washed
with aqueous ammonium chloride (2 x 500 ml, sat.) and water (3 x 500 ml), dried (MgSO
4) and evaporated to give a brownish residue. The crude material was triturated with
CH
2Cl
2, and the solid formed filtered to give compound 6 as a yellow solid (8.0 g, 41%);
1H NMR: (DMSO-d6) 12.30 (b s, 1H), 7.99 (s, 1H), 7.80 (d,
J = 3.0, 1H), 6.71 (d,
J = 3.0, 1H);
LC/MS: (ES+) m/z (M+H)
+ = 231, 233, 235; HPLC R
t = 1.833.
Intermediate 2m
[0234]

[0235] 4-Fluoro-7-Bromo-6-azaindole (500 mg, 1.74 mmol) was dissolved in THF (5ml) and cooled
to -78°C and
n-BuLi (2.5 M, 2.1 ml) was added dropwise. The reaction mixture was stirred at -78°C
for 15 min, then stirred at 0°C for 30 min. The reation was cooled to -78°C again,
and DMF(0.7 ml, 8.7mmol) was added. After stirring for 30 min, water was added to
quench the reaction. The reaction mixture was extracted with ethylacetate. The organic
layer was dried over MgSO
4, filtered, concentrated and chromatographied to afford 208 mg of intermediate 2m.
LC/MS: (ES
+) m/z (M+H)
+ = 164.98. Rt = 0.44 min.
Intermediate 2n
[0236]

[0237] A mixture of intermediate 2m (50 mg, 0.30 mmol), potassium carbonate (42 mg, 0.30
mmol) and tosylmethyl isocyanide (60 mg,0.30 mmol) in MeOH(3ml) was heated to reflux
for about 2 hr. The solvent was removed in vacuum and the residue was treated with
ice water and extracted with ether. The organic layer was washed with an aqueous solution
of HCl (2%), water and dried over magnesium sulfate. After filtration and evaporation
of the solvent, the residue was purified on silica to afford the title compound (60mg).LC/MS:
(ES
+) m/z (M+H)
+ = 204. Rt = 0.77 min.
Intermediate 2o
[0238]

[0239] 4-Fluoro-7-Bromo-6-azaindole (510 mg, 2.39 mmol) in anhydrous DMF (5 mL) was treated
with copper cyanide (430 mg, 4.8 mmol) at 150°C in a seal tube for 1h. An aqueous
solution of NH
4OH (10 mL) was added and the reaction was extracted with diethylether (2 x 50 mL)
and ethylacetate (2 x 50 mL). The organic phases were combined and dried over sodium
sulfate, filtered, concentrated in vacuum and chromatographied on silica gel (gradient
elution AcOEt/Hexanes 0-30%) to afford the title compound as a brownish solid (255
mg, 66%) LC/MS: (ES
+) m/z (M+H)
+ = 162.
Intermediate 2p
[0240]

[0241] Intermediate 2o (82 mg, 0.51 mmol) was dissolved in absolute ethanol (200% proof,
5 mL) and treated with hydroxylamine hydrochloride (53 mg, 0.76 mmol) and triethylamine
(140 µL, 1.0 mmol) and the reaction mixture was heated up at 80°C in a seal tube for
2h. The solvent was removed in vacuum and the pale yellow solid residue was washed
with water to afford the title compound. LC/MS: (ES
+) m/z (M+H)
+ = 195. This compound was taken to the next step without further purification.
Intermediate 2q
[0242]

[0243] Intermediate 2p was dissolved in trimethylorthoformate (1 mL) and heated at 85°C
in a seal tube for 1h, then it was cooled to rt, the solvent was removed in vacuum
and the residue was chromatographied on silica gel (AcOEt/Hexanes, gradient elution
10-60%) to afford the title compound (54 mg, LC/MS: (ES
+) m/z (M+H)
+ =205).
Intermediate 2r
[0244]

[0245] Intermediate 2q (100 mg, 0.62 mmol, crude) in ethanol (5 mL) was treated with an
aqueous solution of sodium hydroxide (50%, 2 mL) and the reaction mixture was heated
at 110°C overnight in a seal tube. The pH was adjusted to 2 with HCl (6N) and a brown
precipitate was filtered off. The solution was concentrated to dryness to afford the
title compound as a pale yellow solid LC/MS: (ES
+) m/z (M+H)
+ =181. This compound was used without further purification.
Intermediate 2s
[0246]

[0247] Intermediate 2r (0.62 mmol) was dissolved in DMF (1 mL) and treated with 3-aminopyridine
(58.3 mg, 0.62 mmol), DEBT (185 mg, 0.62) and Hunig's base (216 µL, 1.26 mmol) and
the reaction mixture was stirred at room temperature for 18h. Water was added and
the reaction was extracted with AcOEt (2 x 25 mL) and CHCl
3 (2 x 25 mL), dried over sodium sulfate, concentrated and chromatographied on silica
gel (AcOEt/Hexanes gradient elution 0-50%) to afford the title compound as a brownish
solid LC/MS: (ES
+) m/z (M+H)
+ =257.
Intermediate 2s
[0248]

[0249] Intermediate 2h, 4-methoxy-7-bromo-5-azaindole was prepared by the same method as
Intermediate 2a, starting from 2-methoxy-5-bromo-4-nitro-pyridine (intermediate 1a).
1H NMR (CDCl3) δ 8.52 (s,1H), 7.84 (s,1H), 7.12 (t, 1H), 6.68 (d, 1H), 3.99 (s, 3H).
LC MS showed desired M+H.
Intermediate 2t
[0250]

[0251] A mixture of aldehyde intermediate
2m (150 mg, 0.91 mmol), sodium cyanide (44mg, 0.091mmol) and tosylmethyl isocyanide
(177 mg, 0.91 mmol) in EtOH(3ml) was stirred at room temperature for 30min, then filtered
and the crystals were washed with ether-hexane (1:1) and dried. The obtained crystals,
and a saturated solution of ammonia in dry methanol (8ml)) were heated between 100-110°C
for 16hr. The mixture was concentrated and chromatographed to provide 20mg of intermediate
2. LC/MS: (ES
+) m/z(m+H)
+ = 203. Rt = 0.64 min.
Intermediate 3a
[0252]

[0253] Typical procedure for acylation of azaindole: Preparation of Methyl (7-chloro-6-azaindol-3-yl)-oxoacetate, Intermediate 3a is an
example of Step B of Scheme 1. 7-Chloro-6-azaindole, Intermediate 2a (0.5 g, 3.3 mmol)
was added to a suspension of AlCl
3 (2.2 g, 16.3 mmol) in CH
2Cl
2 (100 mL). Stirring was continued at rt for 10 minutes before methyl chlorooxoacetate
(2.0 g, 16.3 mmol) was added dropwise. The reaction was stirred for 8 h. The reaction
was quenched with iced aqueous NH
4OAc solution (10%, 200 mL). The aqueous phase was extracted with CH
2Cl
2 (3 x 100mL). The combined organic layer was dried over MgSO
4, filtered and the filtrate was concentrated
in vacuo to give a residue which was carried to the next step without further purification.
Intermediate 2, Methyl (7-chloro-6-azaindol-3-yl)-oxoacetate: MS
m/
z: (M+H)
+ calcd for C
10H
8ClN
2O
3: 239.02; found 238.97. HPLC retention time: 1.07 minutes (column A).
Intermediate 3b
[0254]

[0255] Intermediate 3b, Methyl (6-azaindol-3-yl)-oxoacetate, was prepared by the same method
as Intermediate 3a, starting from 6-azaindole. MS m/z: (M+H)
+ calcd for C
10H
9N
2O
3: 205.06; found 205.14. HPLC retention time: 0.49 minutes (column A).
Intermediate 3c
[0256]

[0257] Intermediate 3c, Methyl (7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetate, was prepared
by the same method as Intermediate 3a, starting from 7-(4-methoxyphenyl)-4-azaindole
(Intermediate 2b). MS
m/
z: (M+H)
+ calcd for C
17H
15N
2O
4: 311.10; found 311.04. HPLC retention time: 1.15 minutes (column A).
Intermediate 3d
[0258]

[0259] Intermediate 3d, methyl (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate was prepared
by the same method as Intermediate 3a, starting from Intermediate 2e, 4-methoxy-7-chloro-6-azaindole.
MS
m/
z: (M+H)
+ calcd for C
12H
12ClN
2O
4: 283.05; found 283.22.
HPLC retention time: 1.37 minutes (column B).
Intermediate 3e
[0260]

[0261] Intermediate 3e, Methyl (7-chloro-4-fluoro-6-azaindol-3-yl)-oxoacetate was prepared
by the same method as Intermediate 3a starting from Intermediate 2d, 4-fluoro-7-chloro-6-azaindole..
1H NMR (500 MHz, CD
3OD) δ 8.63 (s, 1H), 8.00 (s, 1H), 3.95 (s, 3H). MS
m/
z: (M+H)
+ calcd for C
10H
7ClFN
2O
3: 257.01; found 257.00. HPLC retention time: 1.26 minutes (column A).
Intermediate 3f
[0262]

[0263] Intermediate 3f, Methyl (7-chloro-4-azaindol-3-yl)-oxoacetate was prepared by the
same method as Intermediate 3a, starting from Intermediate 2g, 7-chloro-4-azaindole.
MS
m/
z: (M+H)
+ calcd for C
10HClN
2O
3: 239.02; found 238.97. HPLC retention time: 0.60 minutes (column A).
Intermediate 3g
[0264]

[0265] Intermediate 3g, Methyl (5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate was prepared
by the same method as Intermediate 3a, starting from Intermediate 2h, 5-chloro-7-methyl-4-azaindole.
MS
m/
z: (M+H)
+ calcd for C
11H
10ClN
2O
3: 253.04; found 252.97. HPLC retention time: 1.48 minutes (column B).
Intermediate 4a
[0266]

[0267] Typical procedure of hydrolysis of ester: Preparation of Potassium (7-chloro-6-azaindol-3-yl)-oxoacetate, Intermediate 4a,
is an example of Step C of Scheme 1. Crude methyl (7-chloro-6-azaindol-3-yl)-oxoacetate,
Intermediate 3a, and an excess of K
2CO
3 (2 g) were dissolved in MeOH (20 mL) and H
2O (20 mL). After 8 h, the solution was concentrated and the residue was purified by
silica gel column chromatography to provide 200 mg of Potassium (7-chloro-6-azaindol-3-yl)-oxoacetate.
MS
m/
z: (M+H)
+ of the corresponding acid was observed. Calc'd for C
9H
6CIN
2O
3 : 225.01; found 225.05. HPLC retention time: 0.83 minutes (column A).
Intermediate 4b
[0268]

[0269] Potassium (6-azaindol-3-yl)oxoacetate, Intermediate 4b, was prepared by the same
method as Intermediate 4a, starting from Methyl (6-azaindol-3-yl)oxoacetate, Intermediate
3b. MS
m/
z: (M+H)
+ of the corresponding acid was observed. Calc'd for C
9H
7N
2O
3: 191.05; Found 190.99. HPLC retention time: 0.12 minutes (column A).
Intermediate 4c
[0270]

[0271] Intermediate 4c, Potassium (7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetate, was
prepared by the same method as Intermediate 4a, starting from Methyl (7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetate,
Intermediate 3c. MS
m/
z: (M-K+H)
+ calcd for C
16H
13N
2O
4: 297.07; found 297.04. HPLC retention time: 1.00 minutes (column A).
Intermediate 4d
[0272]

[0273] Intermediate 4d, Potassium (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate was prepared
by the same method as Intermediate 4a starting from Methyl (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate,
Intermediate 3d. MS
m/
z: (M+H)
+ of the corresponding acid of compound 4d (M-K+H)
+ calcd for C
10H
8ClN
2O
4: 255.02; found 255.07. HPLC retention time: 0.74 minutes (column A).
Intermediate 4e
[0274]

[0275] Intermediate 4e, Potassium (7-chloro-4-azaindol-3-yl)-oxoacetate was prepared by
the same method as Intermediate 4a, starting from Methyl (7-chloro-4-azaindol-3-yl)-oxoacetate,
Intermediate 3f . MS
m/
z: (M+H)
+ of the corresponding acid of compound 4e (M-K+H)
+ calcd for C
9H
6ClN
2O
3: 225.01; found 225.27. HPLC retention time: 0.33 minutes (column A).
Intermediate 4f
[0276]

[0277] Intermediate 4f, Potassium (5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate was prepared
by the same method as Intermediate 4a, starting from Methyl (5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate,
Intermediate 3g. MS
m/
z: (M+H)
+ of the corresponding acid of compound 4f (M-K+H)
+ calcd for C
10H
8ClN
2O
3: 239.02; found 238.94. HPLC retention time: 1.24 minutes (column B).
Intermediate 4g
[0278]

[0279] Intermediate 4g, Potassium (7-bromo-6-azaindol-3-yl)-oxoacetate was prepared by the
same method as Intermediate 4a, starting from Methyl (7-bromo-6-azaindol-3-yl)-oxoacetate
(prepared according to the method of Intermediate 3a from 7-Bromo-6-azaindole, Intermediate
2f).
1H NMR (500 MHz, DMSO-d
6) δ 8.59 (s, 1H), 8.16 (d, 1H, J = 5.3 Hz), 8.08 (d, 1H, J = 5.45 Hz);
13C NMR (125 MHz, DMSO-d
6) □δ 180.5, 164.0, 141.6,140.4,132.4,125.3,115.5,113.0.
Intermediate 4h
[0280]

[0281] Intermediate 4h, Potassium (7-bromo-4-fluoro-6-azaindol-3-yl)-oxoacetate was prepared
by the same method as Intermediate 4a, starting from Methyl (7-bromo-4-fluoro-6-azaindol-3-yl)-oxoacetate
(prepared according to the method of Intermediate 3a from 7-Bromo-4-fluoro-6-azaindole,
Intermediate 2i). MS
m/
z: (M+H)
+ of the corresponding acid of compound 4g (M-K+H)
+ calcd for C
9H
5BrFN
2O
3: 286.95; found 286.94. HPLC retention time: 0.94 minutes (column A).
Intermediate 4I
[0282]

[0283] 1-ethyl-3-methylimidazolium chloride (0.172 g, 1.1 mmol) was added to aluminum chloride
(0.560 g, 4.2 mmol), and the mixture vigorously stirred. Upon formation of a liquid,
intermediate 2j was added, followed by ethyl chlorooxoacetate (0.12 ml, 1.1 mmol).
The mixture was allowed to stir at r.t. for 16 h, after which additional chlorooxoacetate
was added (0.12 ml, 1.1 mmol). Following this addition, the reaction was allowed to
stir at r.t. for another 24 h. The flask was cooled to 0°C and water added, upon which
precipitates were formed. The solid material was filtered, washed with water and methanol,
and dried under high vacuum to give compound 3;
LC/MS: (ES+) m/z (M+H) = 334, 336; HPLC R
t =1.390.
Intermediate 4j
[0284]

[0285] To 1-ethyl-3-methylimidazolium chloride (2.54 g, 17.3 mmol) was added aluminum chloride
(6.91 g, 51.8 mmol). The mixture was stirred vigorously at ambient temperature for
ten minutes. To the resulting yellow liquid was added intermediate 2k (2.0 g, 8.64
mmol) and ethyl chlorooxoacetate (2.0 ml, 17.3 mmol), and was stirred at ambient temperature
for 16 h. The reaction mixture was then added ice/water (300 ml) to give precipitates,
which were filtered and washed with water to give the title compound as a yellow solid
(1.98 g). The aqueous solution was extracted with EtOAc (3 x 300 ml), and the extracts
evaporated
in vacuo to give a second batch of compound 8 as a yellow solid (439 mg, total yield 92%);
1H NMR: (DMSO-d6) 14.25 (b s, 1H), 13.37 (s, 1H), 8.56 (s, 1H), 8.18 (s, 1H);
LC/MS: (ES+) m/z (M+H)
+ = 303, 305, 307; HPLC R
t = 1.360.
Intermediate 4k
[0286]

[0287] 1-Ethyl-3-methylimidazolium chloride (82mg, 0.56 mmol) was added to a flask which
contained intermediate 2n (56 mg, 0.28 mmol) and the mixture was cooled to 0°C. Aluminum
chloride (336 mg, 2.52 mmol) was added in one portion followed by ClCOCOOEt (58 µL,
0.56 mmol) and the reaction mixture was stirred at room temperature for 2 days. Ice
water was added to quench the reaction. The reaction mixture was filtered. The solid
was washed with water and diethylether and dried in air to afford the title compound
(58mg). LC/MS: (ES
+) m/z (M+H)
+ = 276. Rt = 0.85 min.
Intermediate 4m
[0288]

[0289] 1-Ethyl-3-methylimidazolium chloride (73mg, 0.52 mmol) and aluminum chloride (198
mg, 1.56 mmol) were stirred together under nitrogen for 1h. To this solution was added
intemediate 2q (54 mg, 0.26 mmol) and ethyloxalylchloride (58 µL, 0.52 mmol) and the
reaction mixture was stirred at rt for 18h. The reaction was quenched with water and
the mixture was stirred for 15 min. The solid was collected by filtration and washed
with water and diethylether. LC/MS (ES
+) m/z (M+H)
+ =276. This compound was used without further purification.
Intermediate 4n
[0290]

[0291] 1-Ethyl-3-methylimidazolium chloride (26mg, 0.18 mmol) was added to a flask which
contained intermediate 2t (18 mg, 0.09 mmol) and the mixture was cooled to 0°C. Aluminum
chloride (92 mg, 0.54mmol) was added in one portion followed by ClCOCOOEt (20µL, 0.18
mmol) and the reaction mixture was stirred at room temperature for 2 days. Ice water
was added to quench the reaction. The reaction mixture was filtered. The solid was
washed with water and diethylether and dried in air to afford compound D (18mg). LC/MS:
(ES
+) m/z(m+H)
+ = 275. Rt = 0.49 min.
Intermediate 5a
[0292]

Typical procedure for coupling piperazine derivative and azaindole acid:
[0293] Preparation of 1-benzoyl-3-(R)-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine,
Intermediate 5, is an example of Step D of Scheme 1. Potassium 7-chloro-6-azaindole
3-glyoxylate, Intermediate 4a, (100 mg, 0.44 mmol), 3-(
R)-methyl-1-benzoylpiperazine (107 mg, 0.44 mol), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3
H)-one (DEPBT) (101 mg, 0.44 mol) and Hunig's Base (diisopropylethylamine, 0.5 mL)
were combined in 5 mL of DMF. The mixture was stirred at rt for 8 h. DMF was removed
via evaporation at reduced pressure and the residue was purified using a Shimadzu automated
preparative HPLC System to give 1-(benzoyl)-3-(R)-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazine
(70 mg, 39%). MS
m/
z: (M+H)
+ Calc'd for C
21H
20ClN
4O
3: 411.12; Found 411.06. HPLC retention time: 1.32 minutes (column A).
Intermediate 5b
[0294]

[0295] Intermediate 5b, 1-benzoyl-4-[(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetyl]piperazine
was prepared by the same method as Intermediate 5a starting from Potassium (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate,
Intermediate 4d, and 1-benzoylpiperazine. MS
m/
z: (M+H)
+ calcd for C
21H
20ClN
4O
4: 427.12; found 427.12. HPLC retention time: 1.28 minutes (column A).
Intermediate 5c
[0296]

[0297] Intermediate 5c, 1-benzoyl-3-(R)-methyl-4-[(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetyl]piperazine
was prepared by the same method as Intermediate 5a starting from Potassium (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate,
Intermediate 4d, and 1-benzoylpiperazine.
1HNMR (500 MHz, CDCl
3) δ 8.10 (s, 1H), 7.72 (s, 1H), 7.40 (s, 5H), 3.89 (s, 3H), 3.71 - 3.40 (m, 8H). MS
m/
z: (M+H)
+ calcd for C
22H
22ClN
4O
4: 441.13; found 441.17. HPLC retention time: 1.33 minutes (column A).
Intermediate 5d
[0298]

[0299] Intermediate 5d, 1-benzoyl-3-(R)-methyl-4-[(7-chloro-4-azaindol-3-yl)-oxoacetyl]piperazine
was prepared by the same method as Intermediate 5a, starting from Potassium (7-chloro-4-azaindol-3-yl)-oxoacetate,
Intermediate 4e, and 1-benzoyl-3-(R)-methyl piperazine. MS
m/
z: (M+H)
+ calcd for C
21H
20ClN
4O
3 411.12, found 411.04. HPLC retention time: 1.10 minutes (column A).
Intermediate 5e
[0300]

[0301] Intermediate 5e, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetyl]piperazine
was prepared by the same method as Intermediate 5a, starting from Potassium (5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate,
Intermediate 4f, and 1-benzoyl-3-(R)-methyl piperazine. MS
mlz: (M+H)
+ calcd for C
22H
22ClN
4O
3 425.24, found 425.04. HPLC retention time: 1.72 minutes (column B).
Intermediate 5f
[0302]

[0303] Intermediate 5f, 1-benzoyl-3-(R)-methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine
was prepared by the same method as Intermediate 5a, starting from (7-bromo-6-azaindol-3-yl)-oxoacetic
acid potassium salt, Intermediate 4g, and 1-benzoyl-3-(R)-methylpiperazine. MS
m/
z: (M+H)
+ calcd for C
21H
20BrN
4O
3: 455.07; found 455.14. HPLC retention time: 1.45 minutes (column B).
Intermediate 5g
[0304]

[0305] Intermediate 5g, 1-benzoyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine was
prepared by the same method as Intermediate 5a, starting from (7-bromo-6-azaindol-3-yl)-oxoacetic
acid potassium salt, Intermediate 4g, and 1-benzoylpiperazine. MS
m/
z: (M+H)
+ calcd for C
20H
18BrN
4O
3: 441.06; found 441.07. HPLC retention time: 1.43 minutes (column B).
Intermediate 5h
[0306]

[0307] Intermediate 5h, 1-benzoyl-3-(R)-methyl-4-[(6-azaindol-3-yl)-oxoacetyl]piperazine
was prepared by the same method as Intermediate 5a starting from Potassium (6-azaindol-3-yl)oxoacetate,
Intermediate 4b, and 1-benzoyl-3-(R)-methylpiperazine. MS
m/
z: (M+H)
+ Calc'd for C
21H
21N
4O
3: 377.16; Found 377.10. HPLC retention time: 0.88 minutes (column A).
Intermediate 5i
[0308]

[0309] Addition of intermediate 2d to a solution of aluminum trichloride in dichloromethane
stirring at ambient temperature followed 30 minutes later with chloromethyl or chloroethyl
oxalate (according to the method described for intermediate 3a) provides either the
methyl or ethyl ester, respectively. Hydrolysis with KOH (as in the standard hydrolysis
procedure described for intermediate 4a) provided potassium (7-chloro-4-fluoro-6-azaindol-3-yl)oxoacetate.
Potassium (7-chloro-4-fluoro-6-azaindol-3-yl)oxoacetate was then reacted with 1-benzoyl
piperazine in the presence of DEPBT under the standard conditions (as described for
intermediate 5a) to provide 1-benzoyl-4-[(4-fluoro-7-chloro-6-azaindol-3-yl) oxoacetyl]piperazine,
intermediate 5i.
1H NMR (500 MHz, CD
3OD) δ 8.40 (s, 1H), 8.04 (s, 1H), 7.46 (bs, 5H), 3.80-3.50 (m, 8H); LC/MS (ES
+) m/z (M+H)
+ 415 observed; retention time 1.247 minutes; LC/MS method: YMC ODS-A C18 S7 3.0 x
50 mm column; Start %B = 0, Final %B = 100, Gradient time = 2 minutes; Flow rate =
5 mL/min; detector wavelength = 220 nm.
Intermediate 5j
[0310]

[0311] 1-benzoyl-3-(R)-methyl-4-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazine
was prepared by coupling potassium (7-chloro-4-fluoro-6-azaindol-3-yl)oxoacetate,
prepared as described above for intermediate 5i, with 1-benzoyl-3-(R)-methylpiperazine
in the presence of DEPBT under the standard conditions (as described for intermediate
5a) to provide 1-benzoyl-3-(R)-methyl-4-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]
piperazine, intermediate 5j.
1H NMR (500 MHz, CD
3OD) δ 8.42, 8.37 (s, s, 1H), 8.03 (s, 1H), 7.71-7.45 (m, 5H), 4.72-3.05 (m, 7H), 1.45-1.28
(m, 3H); LC/MS (ES
+) m/z (M+H)
+ 429 observed; retention time 1.297 minutes; LC/MS method: YMC ODS-A C18 S7 3.0 x
50 mm column; Start %B = 0, Final %B = 100, Gradient time = 2 minutes; Flow rate =
5 mL/min; detector wavelength = 220 nm.
Intermediate 5k
[0312]

[0313] Intermediate 5k, 1-benzoyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine was
prepared by the same method as Intermediate 5a, starting from (7-chloro-6-azaindol-3-yl)-oxoacetic
acid potassium salt, Intermediate 4a, and 1-benzoylpiperazine. MS
m/
z: (M+H)
+ calcd for C
20H
18ClN
4O
3: 397.11; found 396.97. HPLC retention time: 2.37 minutes (column F, gradient time
= 3 min, flow rate = 4 ml/min).
Intermediate 51
[0314]

[0315] Intermediate 51, 1-picolinoyl-4-[(4-methoxy-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine
was prepared by the same method as Intermediate 5a starting from Potassium (4-methoxy-7-chloro-6-azaindol-3-yl)oxoacetate,
Intermediate 4d, and picolinoyl-piperazine.
1H NMR (500 MHz, DMSO-d
6) 88.63 - 7.45 (m, 7 H), 3.94 (s, 3H), 3.82 - 2.50 (m, 8H). MS m/z: (M+H)
+ Calc'd for C
20H
19ClN
5O
4: 428.11; Found 428.11. HPLC retention time: 1.09 minutes (column A).
Intermediate 5m
[0316]

[0317] Intermediate 5m, (R)-1-picolinoyl-3- methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine
was prepared by the same method as Intermediate 5a starting from Potassium (7-bromo-6-azaindol-3-yl)oxoacetate,
Intermediate 4g, and (R)-3-methyl-1-picolinoyl-piperazine. MS
m/
z: (M+H)
+ Calc'd for C
20H
19BrN
5O
3: 456.07; Found 456.11. HPLC retention time: 1.12 minutes (column A).
Intermediate 5n
[0318]

[0319] Intermediate 5n, (S)-1-picolinoyl-3- methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine
was prepared by the same method as Intermediate 5a starting from Potassium (7-bromo-6-azaindol-3-yl)oxoacetate,
Intermediate 4g, and (S)-3-methyl-1-picolinoyl-piperazine.
1H NMR (500 MHz, CDCl
3) δ8.63 - 7.36 (m, 7H), 5.02 - 3.06 (m, 7H), 1.42 -1.26 (m, 3H).
Intermediate 5o
[0320]

[0321] Intermediate 5o, (R)-1-picolinoyl-3- methyl-4-[(7-bromo-4-fluoro-6-azaindol-3-yl)-oxoacetyl]piperazine
was prepared by the same method as Intermediate 5a starting from Potassium (7-bromo-4-fluoro-6-azaindol-3-yl)oxoacetate,
Intermediate 4h, and (R)-3-methyl-1-picolinoyl-piperazine.
1H NMR (500 MHz, CD
3OD) δ8.68 - 7.52 (m, 6H), 4.94 - 2.69 (m, 7H), 1.48 -1.24 (m, 3H). MS m/z: (M+H)
+ Calc'd for C
20H
18BrFN
5O
3: 474.06; Found 474.23. HPLC retention time: 1.20 minutes (column A).
Intermediate 5p
[0322]

[0323] Intermediate 5p, 1-benzoyl-4-[(7-chloro-4-azaindol-3-yl)-oxoacetyl]piperazine was
prepared by the same method as Intermediate 5a starting from Potassium (7-chloro-4-fluoro-4-azaindol-3-yl)oxoacetate,
Intermediate
4e, and 1-benzoylpiperazine.
1H NMR (500 MHz, CD
3OD) δ8.83 (s, 1H), 8.63 (d, 1H, J = 5.35 Hz), 7.91 (d, 1H, J = 5.75 Hz), 7.47 (m,
5H), 3.80 - 3.30 (m, 3H). MS
m/
z: (M+H)
+ Calc'd for C
20H
18ClN
4O
3: 397.11; Found 397.02. HPLC retention time: 1.20 minutes (column A).
Intermediate 5q
[0324]

[0325] Intermediate 5q, 1-(4-Benzoyl-piperazin-1-yl)-2-(7-bromo-4-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)-ethane-1,2-dione
To a solution of acid
intermediate 4j (2.4 g, 7.9 mmol) in DMF (40 ml) was added 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3
H)-one (DEPBT, 5.96 g, 19.9 mmol), benzoylpiperazine hydrochloride (2.71 g, 11.9 mmol),
and
N,N-diisopropylethylamine (14 ml, 80.4 mmol). The mixture was stirred at ambient temperature
for 16 h. The reaction mixture was then added water (400 ml) and extracted with EtOAc
(4 x 300 ml). The combined extracts were evaporated
in vacuo to give a brownish residue, which was triturated with MeOH to provide the title compound
as a white solid (2.8 g, 74%);
1H NMR: (DMSO-
d6) 13.41 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H); 7.45 (b s, 5H), 3.80 - 3.35 (b m, 8H);
LC/MS: (ES+) m/z (M+H)
+= 475, 477, 479; HPLC R
t = 1.953.

[0326] Intermediate 5r was prepared by procedure used for 5q using mono N-Boc piperazine .
1H NMR: (CDCl
3) δ 8.26 (s, 1H), 8.19 (s, 1H), 3.71 (b s, 2H), 3.53 (b m, 6H), 1.48 (s, 9H);
LC/MS: (ES+) m/z (M+H)
+= 471, 473, 475; HPLC R
t = 1.543.
Intermediate 6
[0327]

[0328] Typical procedure for N-Oxide formation: Preparation of 1-benzoyl-3-(R)-methyl-4-[(6-oxide-6-azaindol-3-yl)-oxoacetyl]piperazine,
Intermediate 6. 20 mg of 1-benzoyl-3-(R)-methyl-4-[(6-azaindol-3-yl)-oxoacetyl]piperazine,
Intermediate 5h, (0.053 mmol) was dissolved in CH
2Cl
2 (2 mL). 18 mg of mCPBA (0.11 mmol) was then added into the solution and the reaction
was stirred for 12 h at rt. CH
2Cl
2 was removed via evaporation at reduced pressure and the residue was purified using
a Shimadzu automated preparative HPLC System to give the compound shown above (5.4
mg, 26%). MS
m/
z: (M+H)
+ Calc'd for C
21H
21N
4O
4: 393.16; Found 393.11. HPLC retention time: 0.90 minutes (column A).
Intermediate 7
[0329]

[0330] Preparation of 1-benzoyl-3-(R)-methyl-4-[(6-methyl-7-azaindol-3-yl)-oxoacetyl]-piperazine
or 1-benzoyl-3-(R)-methyl-4-[(4-methyl-7-azaindol-3-yl)-oxoacetyl]-piperazine. An
excess of MeMgI (3M in THF, 0.21 ml, 0.63 mmol) was added into a solution of 1-benzoyl-3-(R)-methyl-4-[(6-oxide-6-azaindol-3-yl)-oxoacetyl]piperazine,
Intermediate 6, (25 mg, 0.064 mmol). The reaction mixture was stirred at rt and then
quenched with MeOH. The solvents were removed under vacuum, the residue was diluted
with MeOH and purified using a Shimadzu automated preparative HPLC System to give
a compound shown above which was a single isomer but regiochemistry was not definitively
assigned. (6.7 mg, 27%). MS
m/
z: (M+H)
+ Calc'd for C
22H
23N
4O
3: 391.18; Found 391.17. HPLC retention time: 1.35 minutes (column B).
Intermediate 8
[0331]

[0332] 1-benzoyl-3-(R)-methyl-4-[(6-phenyl-7-azaindol-3-yl)-oxoacetyl]piperazine or 1-benzoyl-3-(R)-methyl-4-[(4-phenyl-7-azaindol-3-yl)-oxoacetyl]piperazine
(regiochemistry was not definitively assigned) were prepared by the method described
for Example 7 starting with 1-benzoyl-3-(R)-methyl-4-[(6-oxide-6-azaindol-3-yl)-oxoacetyl]piperazine,
Intermediate 6, and phenyl magnesium bromide (phenyl Grignard reagent). MS
m/
z: (M+H)
+ Calc'd for C
27H
25N
4O
3: 453.19; Found 454.20. HPLC retention time: 1.46 minutes (column B).
Intermediate 9
[0333]

[0334] A mixture of Pd (10% on carbon, 100 mg), trifluoroacetic acid (1 mL) and 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetyl]piperazine,
Intermediate 5e (1.5 g) in MeOH (50 mL) and EtOAc (50 mL) was shaken in a Parr reactor
under a hydrogen atmosphere (45 psi) for 48 hours. After solids were removed via filtration,
the filtrate was concentrated
in vacuo to afford intermediate 9 (1 g) which was used without further purification. MS
m/
z: (M+H)
+ calcd for C
21H
21N
4O
3 391.18, found 391.15. HPLC retention time: 1.15 minutes (column A).
Intermediates 10 and 11
[0335]

[0336] Preparation of Intermediate 10, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-carbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine
and Intermediate 11, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-hydroxycarbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:
A mixture of 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetyl]piperazine
(1.78 g) and SeO
2 (4.7 g) in dioxane/water (100 : 1) was refluxed for 10 hours. After cooling to room
temperature, the mixture was concentrated
in vacuo to provide a residue. The residue was purified by using silica gel chromatography
with EtOAc and MeOH as eluting solvents to afford intermediate 10 (350 mg) and intermediate
11 (410 mg).
Intermediate 10, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-carbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:
MS
m/
z: (M+H)
+calcd for C
22H
20ClN
4O
4: 439.12, found 439.01. HPLC retention time: 1.37 minutes (column A); Intermediate
11, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-hydroxycarbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:
MS
m/
z: (M+H)
+ calcd for C
22H
20ClN
4O
5: 455.11, found 455.10. HPLC retention time: 1.44 minutes (column A).
Intermediates 12 and 13
[0337]

[0338] Intermediate 12, 1-benzoyl-3-(R)-methyl-4-[(7-carbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine
and Intermediate 13, 1-benzoyl-3-(R)-methyl-4-[(7-hydroxycarbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine
were made according to the same procedure of preparing Intermediates 10 and 11, by
using Intermediate 9 as a starting material. Intermediate 12, 1-benzoyl-3-(R)-methyl-4-[(7-carbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:
MS
mlz: (M+H)
+ calcd for C
22H
21N
4O
4: 405.16, found 405.14. HPLC retention time: 0.91 minutes (column A); Intermediate
13, 1-benzoyl-3-(R)-methyl-4-[(7-hydroxycarbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:
MS m/z: (M+H)
+ calcd for C
22H
21N
4O
5: 421.15, found 421.09. HPLC retention time: 1.02 minutes (column A).
Intermediates 14a-1-14a-21
[0339] The following tin agents and boron agents can be purchased from commercial resources
and used without any further treatment (Table 2).
Table 2
Intermediate Number |
Structure |
Company |
14a-1 |

|
Frontier Scientific, Inc. |
14a-2 |

|
Maybridge Chem. Co. |
14a-3 |

|
Frontier Scientific, Inc. |
14a-4 |

|
Matnx Scientific |
14a-5 |

|
Matrix Scientific |
14a-6 |

|
Aldrich, Co. |
14a-7 |

|
Aldrich, Co. |
14a-8 |

|
Aldrich, Co. |
14a-9 |

|
Aldrich, Co. |
14a-10 |

|
Aldrich, Co. |
14a-11 |

|
Lancaster |
14a-12 |

|
Aldrich, Co. |
14a-13 |

|
Aldrich, Co. |
14a-14 |

|
Frontier Scientific, Inc. |
14a-15 |

|
Matrix Scientific |
14a-16 |

|
Frontier Scientific, Inc. |
14a-17 |

|
Riedel-de Haen AG |
14a-18 |

|
Lancaster |
14a-19 |

|
Lancaster |
14a-20 |

|
Aldrich, Co. |
14a-21 |

|
Frontier Scientific, Inc. |
Preparation of Tin Agents:
Intermediates 14-1-14-65
[0340] The following known tin agents and boron agents could be prepared according to the
documented procedures indicated without any modification (Table 3):
Table 3
Intermediate Number |
Structure |
Reference |
14-1 |

|
Dondoni, A., et al Synthesis, 1987, 693 |
14-2 |

|
Aldous, D. J., et al US - 5,453,433 |
14-3 |

|
Sandosham, J., et al Tetrahedron 1994, 50, 275. |
14-4 |

|
Lehn, L. M., et al. Chem. Eur. J. 2000, 6, 4133. |
14-5 |

|
Jutzi, P., et al J. Organometallic Chem. 1983, 246, 163. |
14-6 |

|
Jutzi, P., et al J. Organometallic Chem. 1983, 246, 163. |
14-7 |

|
Graybill, T. L., et al Bioorg. Med. Chem. Lett. 1995, 5 (4), 387. |
14-8 |

|
Heldmann, D. K., et al Tetrahedron Lett. 1997, 38, 5791. |
14-9 |

|
Kennedy, G., et al Tetrahedron Lett. 1996, 37, 7611. |
14-10 |

|
Kondo, Y., et al Tetrahedron Lett. 1989,30, 4249 |
14-11 |

|
Kondo, Y., et al Tetrahedron Lett. 1989,30, 4249 |
14-12 |

|
Or, Y. S., et al US-6,054,435 |
14-13 |

|
Or, Y.S., et al US-6,054,435 |
14-14 |

|
Okada, T., et al WO-0123383 |
14-15 |

|
Okada, T., et al WO-0123383 |
14-16 |

|
Sandosham, J., et al Tetrahedron 1994, 50, 275 |
14-17 |

|
Sandosham, J., et al Acta Chem. Scand. 1989, 43, 684. |
14-18 |

|
Nicolaou, K. C., et al WO-9967252 |
14-19 |

|
Nicolaou, K. C., et al WO-9967252 |
14-20 |

|
Nicolaou, K. C., et al WO-9967252 |
14-21 |

|
Benheda, R., et al Tetrahedron Lett. 1999, 40, 5701. |
14-22 |

|
Collins, I., et al Tetrahedron Lett. 1999, 40, 4069. |
14-23 |

|
Fuss, R. W., et al DE-19502178 |
14-24 |

|
Bunnage, M.E.et.al PCT Int. Appl. WO 0024745 A1 (2000); and Sandosham, J. et. Al Tetrahedron (1994), 50(1), 275-84. |
14-25 |

|
From 5-iodo2-chloro-1,3 pyrimidine. Fluoropyrimidines are obtained by fluorination
of chloropyrimidines with CsF in N-methyl-2-pyrrolidinone or DMF 2.5-63 h at 80-150
°C. The iodo is then converted to the lithium reagent with tBuLi and trapped with
Bu3SnCl. See Sandosham above. |
14-26 |

|
Arukwe, J.; Benneche, T.; Undheim, K. J. Chem. Soc., Perkin Trans. 1 (1989), (2),
255-9. |
14-27 |

|
Fruit, C.; Heterocycles (1999), 51(10), 2349-2365. |
14-28 |

|
Ziener, U.; et.al. Chem.-Eur. J. (2000), 6(22), 4132-4139. - |
14-29 |

|
Turck, A.; et.al Lab.. J. Organomet. Chem. (1991), 412(3), 301-10. Metallation of 2,6-dicloropyrazine and quench with Bu3SnCl. |
14-30 |

|
Ueno, K.; Sasaki, A.; Kawano, K.; Okabe, T.; Kitazawa, N.; Takahashi, K.; Yamamoto,
N.; Suzuki, Y.; Matsunaga, M.; Kubota, A. PCT Int. Appl. WO 9918077 A1 (1999). |
14-31 |

|
Fensome, A.; Miller, L. L.; Ullrich, J.W.; Bender, RH.W.; Zhang, P.; Wrobel, J.E.;
Zhi, L.; Jones, T.K.; Marschke, K.B.; Tegley, C.M. PCT Int. Appl. WO 0066556 A1 (2000). |
14-32 |

|
Maw, G.N.; Middleton, D.S. Jpn. Kokai Tokkyo Koho JP 2000016984 A2 (2000). Chem. Pharm. Bull. |
14-33 |

|
(1998), 46(3), 400-412. |
14-34 |

|
Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.; Kawafuchi, H. PCT
Int. Appl. WO 9951588 A1 (1999). |
14-35 |

|
Brown, A.D.; Dickinson, RP.; Wythes, M.J. PCT Int. Appl. WO 9321178 A1 (1993). |
14-36 |

|
Brown, A.D.; Dickinson, R.P.; Wythes, M.J. PCT Int. Appl. WO 9321178 A1 (1993). |
14-37 |

|
Zalutsky, M.R. PCT Int. Appl. WHO 0032240 A2 (2000). Brown. A.D.; Dickinson, |
14-38 |

|
Brown, A.D.; Dickinson, R.P.; Wythes, M. J. PCT Int. Appl. WO 9321178 A1 (1993). |
14-39 |

|
North, P.C.; Wadman, S.N. PCT Int. Appl. WO 9408993 A1 (1994). |
14-40 |

|
North, P.C.; Wadman, S.N. PCT Int. Appl. WO 9408993 A1 (1994). |
14-41 |

|
Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. (1993), 34(13), 2127-30. |
14-42 |

|
Muratake, H.; Tonegawa, M.; Natsume, M... Chem. Pharma. Bull. (1998), 46(3), 400-412. Dehmlow, E.V.;Sleegers, A. Liebigs Ann. Chem. (1992), (9), 953-9. |
14-43 |

|
Proudfoot, J.R.; Hargrave, K.; Kapadia, S. PCT Int. Appl. WO 9907379 A1 (1999); and Chem. Pharm. Bull. (1998), 46(3), 400-412. |
14-44 |

|
Cruskie, M.P. Jr.; Zoltewicz, J.A.; Abboud, K.A. J. Org. Chem. (1995), 60(23), 7491-5. |
14-45 |

|
Muratake, H.; et.al Chem. Pharm. Bull. (1998), 46(3), 400-412. |
14-46 |

|
Muratake, H.; Tonegawa, M.; Natsume, M. Chem. Pharm. Bull. (1998), 46(3), 400-412. Dolle, RE.; Graybill, T.L.; Osifo, I.K.; Harris, A.L.; Miller, M.S.; Gregory, J.S.
U.S. US 5622967(1997). |
14-47 |

|
Henze, O.; Lehmann, U.; Schlueter, A.D. Synthesis (1999), (4), 683-687. |
14-48 |

|
Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.; Kawafuchi, H. PCT
Int. Appl. WO 9951588 A1 (1999); Reuman, M.; Daum, S.J.; Singh, B.; Wentland, M.P.; Perni, R.B.; Pennock, P.; Carabateas,
P.M.; Gruett, M.D.; Saindane, M.T.; et al. J. Med. Chem. (1995), 38(14), 2531-40. |
14-49 |

|
Barros, M.T.; Maycock, C.D.; Ventura, M.R. Tetrahedron Lett. (1999), 40(3), 557-560. Sirisoma, N.S.; Johnson, C.R. Tetrahedron Lett. (1998), 39(15), 2059-2062. Trost, B.M.; Cook, G.R Tetrahedron Lett. (1996), 37(42), 7485-7488. |
14-50 |

|
Bunnage, M.E.; Maw, G.N.; Rawson, D.J.; Wood, A.; Mathias, J.P.; Street, S.D.A. PCT
Int. Appl. WO 0024745 A1 (2000). |
14-51 |

|
Bunnage, M.E.; Maw, G.N.; Rawson, D.J.; Wood, A.; Mathias, J. P.; Street, S.D.A. PCT
Int. Appl. WO 0024745 A1 (2000). |
14-52 |

|
Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.; Kawafuchi, H. PCT
Int Appl. WO 9951588 A1 (1999); and Sirisoma, N.S.; Johnson, C.R Tetrahedron Lett. (1998), 39(15), 2059-2062. |
14-53 |

|
Schnatterer, S.; Kern, M.; Sanft, U. PCT Int. Appl. WO 9965901 A1 (1999). |
14-54 |

|
Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.; Kawafuchi, H. PCT
Int. Appl. WO 9951588 A1 (1999). |
14-55 |

|
Betagen, R.; Breitfelder, S.; Cirillo, P.F.; Gilmore, T.A.; Hickey, E.R.; Kirrane,
T.M.; Moriak, M.H.; Moss, N.; Patel, U.R.; Proudfoot, J.R.; Regan, J.R.; Sharma, R.;
Sun, S.; Swinamer, A.D.; Takahashi, H. PCT Int. Appl. WO 0055139 A2 (2000). |
14-56 |

|
Ueno, K.; Sasaki, A.; Kawano, K.; Okabe, T.; Kitazawa, N.; Takahashi, K.; Yamamoto,
N.; Suzuki, Y.; Matsunaga, M.; Kubota, A. PCT Int. Appl. WO 9918077 A1 (1999). |
14-57 |

|
Calderwood, D.; Arnold, L.D.; Mazdiyasni, H.; Hirst, G.; Deng, B.B. PCT Int. Appl.
WO 0017202 A1 (2000). |
14-58 |

|
Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.; Kawafuchi, H. PCT
Int. Appl. WO 9951588 A1 (1999). |
14-59 |

|
Saji, H.; Watanabe, A.; Magata, Y.; Ohmono, Y.; Kiyono, Y.; Yamada, Y.; Iida, Y.;
Yonekura, H.; Konishi, J.; Yokoyama, A. Chem. Pharm. Bull. (1997), 45(2), 284-290. |
14-60 |

|
Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.; Kawafuchi, H. PCT
Int. Appl. WO 9951588 A1 (1999); Reuman, M.; Daum, S.J.; Singh, B.; Wentland, M.P.; Perni, R.B.; Pennock, P.; Carabateas,
P.M.; Gruett, M.D.; Saindane, M.T.; et al. J. Med. Chem. (1995), 38(14), 2531-40. |
14-61 |

|
Iino, Y.; Fujita, K.; Kodaira, A.; Hatanaka, T.; Takehana, K.; Kobayashi, T.; Konishi,
A.; Yamamoto, T. PCT Int. Appl. WO 0102359 A1 (2001). |
14-62 |

|
Iino, Y.; Fujita, K.; Kodaira, A.; Hatanaka, T.; Takehana, K.; Kobayashi, T.; Konishi,
A.; Yamamoto, T. PCT Int. Appl. WO 0102359 A1 (2001). |
14-63 |

|
Torrado, A.; Imperiali, B. J. Org. Chem. (1996), 61(25), 8940-8948. |
14-64 |

|
Iino, Y.; Fujita, K.; Kodaira, A.; Hatanaka, T.; Takehana, K.; Kobayashi, T.; Konishi,
A.; Yamamoto, T. PCT Int. Appl. WO 0102359 A1 (2001). |
14-65 |

|
Gros, P.; Fort, Y. Synthesis (1999), (5), 754-756 and Gros, P.; Fort, Y.; Caubere, P. J. Chem. Soc., Perkin Trans. 1 (1997), (20), 3071-3080. |
Intermediate 14-66
[0341]

[0342] Preparation of 2,3-dicloro-5-(tri-n-butylstannyl)pyrazine (An example of general
procedure Tin-01, below): TMP-Li (2,2,6,6-tetramethylpiperidinyl lithium) was prepared
by addition of n-butyl lithium (1.6 M, 6.25 mL) to a solution of 2,2,4,4-tetramethylpiperidine
(1.4 g) in dry THF (180 mL) at -78 °C. The solution was then allowed to warm to 0
°C, was stirred at 0 °C for 15 minutes, then was cooled to -78 °C. To the solution
was added 2,3-dichloropyrazine (1.35 g), and followed by an addition of tri-n-butyltin
chloride (3.25 g) in another 2 hours. The reaction was quenched with aqueous ammonium
chloride solution. The organic layer was separated, and aqueous layer was extracted
with ethyl acetate (3 x 100 mL). The combined organic extract was dried over magnesium
sulfate, filtered and the filtrate concentrated
in vacuo. The residue was purified by silica gel chromatography to afford 2,3-dicloro-5-(tri-n-butylstannyl)pyrazine
(1 g).
Intermediate 14-67
[0343]

[0344] Preparation of 2-(tri-n-butylstannyl)-pyrimidine: (Example of the general procedure
Tin-03, below) Tri-n-butylstannyl lithium was prepared at 0 °C in dry THF (20 mL)
from tri-butyltin hydride (2.2 mL) and LDA (lithium diisopropylamide, 2M, 4.09 mL).
The tri-n-butylstannyl lithium solution was then cooled to -78 °C and to it was added
2-bromopyrimidine (1 g). The reaction The mixture was then allowed to warm up to room
temperature over 8 hours. reaction was then quenched with aqueous ammonium chloride
solution. The organic layer was separated, and aqueous layer was extracted with ethyl
acetate (3 x 20 mL). The combined organic layer was dried over magnesium sulfate,
filtered and the filtrate concentrated
in vacuo. The residue was purified by silica gel chromatography to afford 2-(tri-n-butylstannyl)-pyrimidine
(190 mg).
Intermediate 14-68
[0345]

[0346] Preparation of 2-amino-6-(tri-n-butylstannyl)pyrazine (Example of the general procedure
Tin-04, below): To a sealed tube, 2-amino-6-chloro-pyrazine (1 g), bis(tri-butyltin)
(3.92 mL) and tetrakis-triphenylphosphine palladium, Pd(Ph
3P)
4 (100 mg) were combined in dioxane (10 mL). The reaction was heated at 110-120 °C
for 10 h. After the mixture cooled down to room temperature, it was poured into 20
mL of water. The solution was extracted with EtOAc (4 x 20 mL). The combined extract
was concentrated
in vacuo to give a residue which was purified by silica gel chromatography to afford 2-amino-6-(tri-n-butylstannyl)pyrazine
(0.5 g)
Intermediate 14-69
[0347]

[0348] Preparation of 2-methylsulfonylamino-5-(tri-n-butylstannyl)pyrazine (Example of general
procedure Thin-05, below): NaH (60%, 20 mg) was added into a solution of 2-amino-5-(tri-n-butylstannyl)pyrazine
(0.2 g) in THF (30 mL) at room temperature. After the mixture stirred at room temperature
for 30 minutes, to it was added methylsulfonyl chloride (63 mg). The reaction mixture
was stirred at room temperature over 8 hours. The reaction was quenched with aqueous
ammonium chloride solution. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate (3 x 100 mL). The combined organic extract was dried
over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue
was purified by silica gel chromatography to afford 2-methylsulfonylamino-5-(tri-n-butylstannyl)pyrazine
(20 mg).
Intermediates 14-70 - 14-129
[0349] The intermediates 14-70 - 14-129 were prepared according to the following general
procedures designated Tin-01 through Thin-05.
General Procedure Tin-01:
[0350]

[0351] To a solution of a base (1.1 equivalents) selected from lithium diisopropylamide,
2,2,6,6-tetramethylpiperidinyl lithium, n-butyl lithium, sec-butyl lithium or tert-butyl
lithium in a solvent selected from tetrahydrofuran, diethyl ether or dimethoxyethane
(concentration of approximately 0.05 mmol base/mL of solvent) at -78 °C was added
an appropriate aryl or heteroaryl substrate (1.0 equivalents) followed by an addition
of tri-n-butyltin chloride or trimethyltin chloride (1.1 equivalents) in another 2
hours. The reaction was quenched with aqueous ammonium chloride solution. The organic
layer was separated, and aqueous layer was extracted with ethyl acetate. The combined
organic extract was dried over magnesium sulfate, filtered and the filtrate concentrated
in vacuo. The residue was purified by silica gel chromatography to afford the desired stannane.
General Procedure Tin-02:
[0352]

[0353] To a solution of a base (1.1 equivalents) selected from n-butyl lithium, sec-butyl
lithium or tert-butyl lithium in a solvent selected from tetrahydrofuran, diethyl
ether or dimethoxyethane (concentration of approximately 0.05 mmol base/mL of solvent)
at -78 °C was added an appropriate aryl or heteroaryl bromide or aryl or heteroaryl
iodide substrate (1.0 equivalents). The reaction mixture was stirred at -78 °C for
a period suitable to generate the anion via metal-halogen exchange then to it was
added tri-n-butyltin chloride or trimethyltin chloride (1.1 equivalents). The reaction
was quenched with aqueous ammonium chloride solution. The organic layer was separated,
and aqueous layer was extracted with ethyl acetate. The combined organic extract was
dried over magnesium sulfate, filtered and the filtrate concentrated
in vacuo. The residue was purified by silica gel chromatography to afford the desired stannane.
General Procedure Tin-03:
[0354]

[0355] Tri-n-butylstannyl lithium or trimethylstannyl lithium (1.3 equivalents) was prepared
at 0 °C in dry solvent selected from THF, diethyl ether or dimethoxyethane (20 mL)
from tri-n-butyltin hydride or trimethyltin hydride, respectively (1.3 equivalents)
and LDA (lithium diisopropylamide, 1.3 equivalents) at a concentration of approximately
0.4 mmol of alkylstannyl lithium/mL of solvent. The tri-n-butylstannyl lithium or
trimethylstannyl lithium solution was then cooled to -78 °C and to it was added an
appropriate haloaryl or haloheteroaryl substrate (1.0 equivalent). The reaction mixture
was then allowed to warm up to room temperature over 8 hours. The reaction was then
quenched with aqueous ammonium chloride solution. The organic layer was separated,
and aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic
layer was dried over magnesium sulfate, filtered and the filtrate concentrated
in vacuo. The residue was purified by silica gel chromatography to afford the desired stannane
intermediate.
General Procedure Tin-04:
[0356]

[0357] To a sealed tube, an appropriate aryl or heteroaryl substrate (1.0 equivalent), bis(tri-butyltin)
or hexamethylditin (1.0 equivalent) and tetrakis-triphenylphosphine palladium, Pd(Ph
3P
4) (1.0 mol%) were combined in dioxane or toluene (10 mL). The reaction was heated
at 110-120 °C for 10 h. After the mixture cooled down to room temperature, it was
poured into water. The solution was extracted with ethyl acetate and the combined
extracts were concentrated
in vacuo to give a residue which was purified by silica gel chromatography to afford the desired
stannane product.
General Procedure Tin-05:
[0358] The following general reaction scheme depicts the derivatization of stannane intermediates
in which the stannane has a reactive ring NH group or reactive exocyclic amino, hydroxy
or thiol group. The starting stannane is treated with base in an appropriate solvent
then is reacted with suitable electrophiles such as alkyl halides, acid chlorides,
sulfonyl chlorides, isocyanates and the like.

[0359] An appropriate base selected from sodium hydride, n-butyl lithium, lithium diisopropylamide,
potassium carbonate, triethylamine, DBU, DMAP or sodium hexamethyldisilazide (1.0
equivalent) was added into a solution of an appropriate stannane substrate (as depicted
above, 1.0 equivalent) in an appropriate solvent selected from dichloromethane, THF,
diethyl ether or N,N-dimethylformamide at a temperature between -78 °C and room temperature.
After the mixture stirred for a period sufficient to allow deprotonation, typically
for 5 to 30 minutes, then to it was added an appropriate electrophile such as an alkyl
halide, acid chloride, sulfonyl (1.0 equivalent). The reaction mixture was stirred,
typically at room temperature, over a period of 2 to 8 hours. The reaction was quenched
with aqueous ammonium chloride solution. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic
extract was dried over magnesium sulfate, filtered and the filtrate was concentrated
in vacuo. The residue was purified by silica gel chromatography to afford the desired
stannane intermediate.
General procedure Tin-06
[0360]

[0361] An aryl hilide stannane agent was dissolved in appropriate alcohol, either methanol
or ethanol. After a cataylst (pt or pd) was added into the solvent, the reaction mixture
is placed in an environment of hydrogen under normal or raised pressure. After reaction
finishes, the catalyst is filtered, and, concentration of the mother solution provides
a residue which is used in the further reactions without any purification.
Rf = retention time
Intermed. Number |
Structure |
Starting Material |
Method Applied |
Identification |
14-70 |

|

|
Tin-04 |
Rf = 2.33 min (Column A) 1H NMR (500 MHz, CDC13) δ 4.00 (s, 6H), 1.63 - 0.85 (m, 27H) |
14-71 |

|

|
Tin-01 |
Rf = 2.52 mm Column A) H NMR (300 MHz, CDCl3) δ 7.02 (s, 1H), 4.44 (q, 2H, J= 7.02 Hz), 1.63 - 0.85 (m, 30H) |
14-72 |

|

|
Tin-01 |
Rf = 2.84 min Column B) H NMR (500 MHz, CDC13) δ 9.48 (s, 1H), 8.45 (s, 1H), 2.03 -
0.88 (m, 36H) |
14-73 |

|

|
Tin-05 |
Rf = 2.27 min (Column A) 1H NMR (500 MHz, CDCl3) δ 7.53 (m, 1H), 6.29 (m, 1H), 3.94 (s, 3H), 1.56-0.87 (m, 27H) |
14-74 |

|

|
Tin-05 |
Rf = 2.22 min (Column A) |
14-75 |

|

|
Tin-01 |
Rf = 2.44 min (Column B) H NMR (500 MHz, CDCl3) δ 8.89 (s, 1H), 8.34 (s, 1H), 1.61 - 0.85 (m, 27H) |
14-76 |

|

|
Tin-01 |
Rf = 3.41 mm (Column A, flow rate = 4 ml/min) 1H NMR (300 MHz, CDCl3) δ 8.58 (d, 1H, J = 2.52 Hz), 8.13 (d, 1H, J= 2.52 Hz), 1.63 - 0.85 (m, 27H) |
14-77 |

|

|
Tin-01' |
Rf = 3.89 min (Column A, flow rate = 4 ml/min) 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 1.61-0.85 (m, 27H) |
14-78 |

|

|
Tin-01 |
Rf = 3.86 min (Column A, flow rate = 4 ml/min) 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 1.61-0.85 (m, 27H) |
14-79 |

|

|
Tin-04 |
Rf = 2.10 min (Column B) 1H NMR (500 MHz, CDCl3) δ 7.90 (s, 1H), 7.26 (s, 1H), 1.58-0.87 (m, 27H) |
14-80 |

|

|
Tin-04 |
Rf = 1.83 min (Column A) |
14-81 |

|

|
Tin-04 |
Rf = 1.84 min (Column A) |
14-82 |

|

|
Tin-04 |
Rf = 1.84 min (Column A) |
14-83 |

|

|
Tin-04 |
Rf = 1.90 min (Column A) |
14-84 |

|

|
Tin-01 |
Rf = 2.23 min (Column A) |
14-85 |

|

|
Tin-04 |
Rf = 1.92 min (Column A) |
14-86 |

|

|
Tin-03 |
Rf = 2.01 min (Column A) |
14-87 |

|

|
Tin-01 |
Rf = 2.45 min (Column A) |
14-88 |

|

|
Tin-01 |
Rf = 2.61 min (Column C) |
14-89 |

|

|
Tin-01 |
Rf = 2.31 min (Column C) |
14-90 |

|

|
Tin-04 |
Rf = 2.71 min (Column D) |
14-91 |

|

|
Tin-01 |
Rf = 2.49 min (Column C) |
14-92 |

|

|
Tin-01 |
Rf = 2.42 min (Column C) |
14-93 |

|

|
Tin-01 |
Rf = 3.49 min (Column C) Flow Rate = 4 ml/min |
14-94 |

|

|
Tin-01 |
Rf = 2.46 min (Column C) |
14-95 |

|

|
Tin-05 |
Rf = 2.15 min (Column A) |
14-96 |

|

|
Tin-01 |
Rf = 2.28 min (Column C) |
14:97 |

|

|
Tin-01 |
Rf = 2.60 min (Column C) |
14-98 |

|

|
Tin-01 |
Rf = 2.37 min (Column A) |
14-99 |

|

|
Tin-01 |
Rf = 2.59 min (Column A) |
14-100 |

|

|
Tin-01 |
Rf = 2.49 min (Column C) |
14-101 |

|

|
Tin-04 |
Rf = 2.41 min (Column A) |
14-102 |

|

|
Tin-04 |
Rf = 1.18 min (Column E) |
14-103 |

|

|
Tin-04 |
Rf = 1.92 min (Column E) |
14-104 |

|

|
Tin-04 |
Rf = 2.01 min (Column E) |
14-105 |

|

|
Tin-04 |
Rf = 2.15 min (Column E) |
14-106 |

|

|
Tin-04 |
Rf = 1.91 min (Column E) |
14-107 |

|

|
Tin-04 |
Rf = 1.95 min (Column A) |
14-108 |

|

|
Tin-04 |
Rf = 1.93 min (Column A) |
12-109 |

|

|
Tin-01 |
Rf = 1.95 min (Column A) |
14-110 |

|

|
Tin-01 |
Rf = 1.83 min (Column A) H NMR (500 MHz, CDCl3) δ 9.03 (d, 1H, J = 5.15 Hz), 7.49
(d, 1H, J = 7.95 Hz), 7.26 (m, 1H), 1.61 - 0.86 (m, 27H); 13C NMR (125 MHz, CDCl3) δ 175.3, 149.8, 133.2, 123.7, 29.0, 27.3, 13.6, 10.1. |
14-111 |

|

|
Tin-01 |
Rf = 2.18 min Column E) 1H NMR (500 MHz, CDCl3) δ 9.22 (s, 1H), 8.46 (d, 1H, J = 4.80 Hz), 7.42 (d, 1H, J =
4.75 Hz), 1.56 - 0.86 (m, 27H); 13C NMR (125 MHz, CDC13) δ 185.4, 158.0, 153.2, 130.6, 28.9, 27.2, 13.5, 9.9. |
14-112 |

|

|
Tin-04 |
Rf = 1,96 min (Column A) |
14-113 |

|

|
Tin-01 |
Rf = 2.61 min (Column A) |
14-114 |

|

|
Tin-01 |
Rf = 2.85 min (Column A) |
14-115 |

|

|
Tin-05 |
Rf = 2.09 min (Column A) 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 7.95 (s, 1H), 4.11 (s, 1H), 2.95 (s, 3H), 2.03
- 0.85 (m, 27H) |
14-116 |

|

|
Tin-05 |
Rf = 2.16 min Column A) H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.92 (s, 1H), 4.49
(s, 1H), 3.35 (m, 2H), 1.63-0.85 (m, 30H) |
14-117 |

|

|
Tin-04 |
Rf = 2.19 min (Column A) |
14-118 |

|

|
Tin-04 |
Rf = 2.18 min (Column A) |
14-119 |

|

|
Tin-04 |
Rf = 2.47 min (Column A) 1H NMR (500 MHz, CDCl3) δ 7.85 (s, 1H), 4.91 (s, 2H), 2.16 - 0.87 (m, 27H) |
14-120 |

|

|
Tin-04 |
Rf = 2.61 min (Column A) |
14-121 |

|

|
Tin-04 |
Rf = 2.92 min (Column A) |
14-122 |

|

|
Tin-04 |
Rf = 1.93 min (Column A) |
14-123 |

|

|
Tin-01 |
Rf = 2.20 min (Column A) |
14-124 |

|

|
Tin-01 |
Rf = 2.50 min (Column A) 1H NMR (500 MHz, CDCl3) δ 9.07 (s, 1H), 7.87 (s, 1H), 1.59 - 0.85 (m, 27H) |
12-125 |

|

|
Tin-04 |
Rf = 1.97 min (Column A) |
14-126 |

|

|
Tin-04 |
Rf = 1.9 min (Column A) |
14-127 |

|

|
Tin-01 |
Rf = 2.70 min (Column E) 1H NMR (500 MHz, CDCl3) δ 8.11 (d, 1H, J = 5.2 Hz), 7.41 (d, 1H, J = 5.2 Hz), 6.94
(s, 1H), 1.62 - 0.89 (m, 27H) |
14-128 |

|

|
Tin-06 |
1H NMR (500 MHz, CDCl3) δ 8.12 (d, 1H, J = 5.2 Hz), 7.78 (s, 1H), 7.46 (d, 1H, J =
5.2 Hz), 6.84 (s, 1H), 1.98 - 0.85 (m, 27H) |
14-129 |

|

|
Tin-01 |
Rf = 1.86 min (Column A) |
|
|
|
|
|
[0362] The following table contains novel stannane reagents which can be prepared by the
methodology described above and then could be used to prepare compounds of formula
I
Table 3
Intermediate Number |
Structure |
Reference |
|

|
From 5-iodo2-chloro-1,3 pyrimidine. Fluoropyrimidines are obtained by fluorination
of chloropyrimidines with CsF in N-methyl-2-pyrrolidinone or DMF 2.5-63 h at 80-150□.
The iodo is then converted to the lithium reagent with tBuLi and trapped with Bu3SnCl.
See Sandosham above. |
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Turck, A.; et.al Lab.. J. Organomet. Chem. (1991), 412(3), 301-10. Metallation of 2,6-dicloropyrazine and quench with Bu3SnCl |
|

|
Analogous to Lehn, L. M., et al. Chem. Eur. J. 2000, 6, 4133. |
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Metallation ot 1-trityl-4-iodo imidazole (prepared in Takahashi, Kazuyuki; Kirk, Kenneth L.; Cohen, Louis A. Lab. Chem., Natl. Inst. Arthritis
Diabetes Dig. Kidney Dis., Bethesda, MD, USA. J. Labelled Compd. Radiopharm. (1986),
23(1), 1-8) using tBuLi in THF at -78 and quenching with Bu3SnCl. Detritylate with TFA or aq HCl after coupling to azaindole core. |
|

|
Metallation of 1-methyl-4-iodo imidazole (prepared in Takahashi, Kazuyuki; Kirk, Kenneth L.; Cohen, Louis A. Lab. Chem., Natl. Inst. Arthritis
Diabetes Dig. Kidney Dis., Bethesda, MD, USA. J. Labelled Compd. Radiopharm. (1986),
23(1), 1-8) using tBuLi in THF at -78 and quenching with Bu3SnCl. El Borai, M.; Moustafa, A. H.; Anwar, M.; Abdel Hay, F.I. The bromo derivative
is described in Pol. J. Chem. (1981), 55(7-8), 1659-65 and can be used to generate the tin reagent via transmetallation. |
|

|
|
|

|
4,5 difluoromidazole prepared as in Dolensky, Bohumil;et.al, USA. J. Fluorine Chem. (2001), 107(1), 147-148. |
|

|
Dolensky, Bohumil;et.al, USA. J. Fluorine Chem. (2001), 107(1), 147-148. |
|

|
|
Select general procedures, via SNAr reactions, for the preparation of starting materials for Tin agents
a. Preparation of 2-bromo-5-substituted-pyrazine, 5-bromo-2-subsituted-thiazole, 2-substituted-thiazaole,
4-chloro-6-substituted-pyrimidine and 5-bromo-2-substituted-pyrimide
[0364] To a flask, an appropriate pyrazine, pyrimidine or thiazole (1.0 equivalent) and
a nucleophile, such as amine, alcohol or thio-derivatives in one equivanlence or an
exess amount were combined in a solvent such as THF, DMF or alcohol, with or without
an addition of NaH. The reaction was either stirred at room temperature or under heating
for one to three days. After all the solvents were removed, the residue was partitioned
between saturated NaHCO
3 and EtOAc. The aqueous layer was extracted with ethyl acetate and the combined extracts
were concentrated
in vacuo to give a residue, which was purified by silica gel chromatography to afford the
desired product.
Starting Material |
Product |
Reaction Condition |
Rf (minutes) |
MS (M+H)+ Cald. |
MS (M+H)+ Obsv. |

|

|
SM-01 (2g) Piperazine (10 g), THF (50 ml), r.t. |
0.5b (column G) |
243.02 |
243.03 |

|

|
SM-01 (1 g), MeNH2 (2M in THF, 100 ml), r.t. |
0.89 (column E) |
187.93 |
187.98 |

|

|
SM-01 (1g ), Me2NH (2M in THF, 100 ml), r.t. |
1.19 (column E) |
201.92 |
202.00 |

|

|
SM-01 (1 g), MeONa (0.5M in MeOH, 100 ml), r.t. |
1.05 (column E) |
189.91 |
188.97 |

|

|
SM-01 (50 mg), NaH (17 mg), 2-amino-1,3,4-thiadiazole (25 mg), DMF 5 ml) r.t. |
1.21 (column E) |
257.94 |
257.89 |

|

|
SM-01 (50 mg), NaH (17 mg), N-benzylpiper azine (25 mg), DMF 5 ml) r.t. |
1.04 (column E) |
333.07 |
332.99 |

|

|
SM-01 (50 mg), NaH (17 mg), N,N-diethylami no-ethanol (0.033 ml), DMF 5 ml) r.t. |
0.72 (column E) |
214.06 |
273.97 |

|

|
SM-02 (2 g) Piperazine (10 g), THF (50 ml), r.t. |
0.89 (column E) |
247.99 |
247.97 |

|

|
SM-05 (1 g), Me2NH (2M in THF, 100 ml), r.t. |
0.65 (column E) |
206.89 |
206.96 |

|

|
SM-02 (1 g), MeONa (0.5M in MeOH, 100 ml), r.t. |
1.35 (column E) |
193.93 |
193.84 |

|

|
SM-03 (50 mg), NaH (16 mg), imidazole (77 mg), DMF 5 ml) r.t. |
0.89 (column E) |
229.94 |
229.83 |

|

|
SM-02 (50 mg), NaH (16 mg), N-benzylpiper azine (30 mg), DMF 5 ml) r.t. |
1.02 (column E) |
338.03 |
337.98 |

|

|
SM-02 (50 mg), NaH (16 mg), N,N-diethylami no-ethanol (0.033 ml), DMF 5 ml) r.t. SM-03
(50 |
0.83 (column E) |
279.02 |
278.95 |

|

|
mg), NaH (25 mg), imidazole (25 mg), DMF 5 ml) r.t. |
0.31 (column E) |
151.91 |
152.03 |

|

|
SM-03 (50 mg), NaH (25 mg), N-benzylpiper azine (37 mg), DMF 5 ml) r.t. |
0.66 (column E) |
260.07 |
260.12 |

|

|
SM-03 (50 mg), NaH (25 mg), N,N-diethylami no-ethanol (0.05 ml), DMF 5 ml) r.t. |
0.46 (column E) |
201.11 |
201.02 |

|

|
SM-04 (1g), MeONa (0.5M in MeOH, 13.52 ml), r.t. |
0.86 (column E) |
145.02 |
144.99 |

|

|
SM-04 (1g), MeNH2 (2M in THF, 100ml), r.t. |
0.46 (column E), |
144.03 |
143.96 |

|

|
SM-05 (1g), MeONa (0.5M in MeOH, 100ml), 1 day, r.t. |
0.91 (column E) |
188.97 |
188.91 |

|

|
SM-05 (1g), MeNH2 (2M in THF, 100 ml), r.t. |
0.84 (column E) |
187.99 |
187.94 |

|

|
SM-05 (1g), Me2NH (2M in THF, 100 ml), r.t. |
1.24 (column E) |
202.00 |
201.98 |
b. Preparation of 2-bromo-5,6-disubstituted-pyrazine
[0365]

Step one
[0366] To a flask, an appropriate pyrazine (1.0 equivalent) and a nucleophile, such as amine
or sodium alkoxide in an exess amount were combined in a solvent such as water or
THF or without solvent. The reaction was either stirred at room temperature or under
heating for one to three days. After all the solvents were removed, a residue was
collected and used in the further steps without any purification.
Starting Material |
Product |
Redaction Condition |
Rf (minutes) |
MS (M+H)+ Cald. |
MS (M+H)+ Obsv. |

|

|
SM-06 (100 mg), propylamine (2 ml), r.t. |
1.28 (column C) |
172.06 |
172.09 |

|

|
SM-06 (100 mg), Me2NH (2M in THF, 10 ml) or Me2NH (40% in water, 10 ml), r.t. |
1.21 (column C) |
158.05 |
158.07 |

|

|
SM-06 (100 mg), Me2NH (40% in water, 10 ml), 100°C |
0.49 (column C) |
167.13 |
167.19 |

|

|
SM-V6 (100 mg), MeNH2 (2M in THF, 10 ml), r.t. |
0.72 (column C) |
144.03 |
144.07 |

|

|
SM-06 (100 mg), NH40H (10 ml), 100°C |
0.41 (column C) |
162.04 (M+Me OH+H)+ |
162.06 (M+MeO H+H)+ |
Step two
[0367] To a flask, the crude pyrazine derivative obtained from the step one (1.0 equivalent)
and a nucleophile, such as amine or sodium alkoxide in an exess amount were combined
in a solvent such as water or THF or without solvent. The reaction was either stirred
at room temperature or under heating for one to three days. After all the solvents
were removed, a residue was collected and used in the further steps without any purification.
Starting Material |
Product |
Reaction Condition |
Rf (minutes) |
MS (M+H)+ Cald. |
MS (M+H)+ Obsv. |

|

|
SM-07 (2 g), MeONa (12.5 wt%, 100ml, 100°C |
0.28 (column C) |
140.08 |
140.14 |

|

|
SM-08 (2 g), MeONa (12.5 wt%, 20ml), 100°C |
0.28 (column C) |
158.13 |
158.09 |

|

|
SM-07 (2 g), MeNH2 (40% in water, 100 ml), 110°C |
0.34 (column C) |
139.10 |
139.13 |
Step three
General procedure of the preparation of 2-alkyl-5-bromo-pyrimide:
[0369]

[0370] To a sealed tube, 5-bromo-2-iodopyrimidine (1.0 equivalent), tri-alkylalumimun (1.5
equivalent) and tetrakis-triphenylphosphine palladium, Pd(Ph
3P)
4 (1.0 mol%) were combined in dioxane(10 mL). The reaction was heated at 110-120 °C
for 10 h. After the mixture cooled down to room temperature, it was poured into water.
The solution was extracted with ethyl acetate and the combined extracts were concentrated
in vacuo to give a residue which was purified by silica gel chromatography to afford the desired
2-alkyl-5-bromopyrimidine product.
R3Al |
Product |
Rf (minutes) |
MS (M+H)+ Cald. |
MS (M+H)+ Obsv. |
Me3Al |

|
0.90 (column E) |
172.94 |
172.97 |
(1-Hu)3Al |

|
1.45 (column E) |
215.02 |
214.99 |
Prep of triazine stannane for Stille coupling to prepare examples of claim 1. (the
sulfur can thenbe removed with Raney Nickel to give additional desulfurized triazines)

2,2,6,6-tetramethylpiperidine (2.0ml, 11.81mmol) in 30ml of THF was cooled to - 78oC
and treated with n-butyllithium (4.7ml), 11.81mmol, 2.5M in hexane). After stirring
30min at 0oC, the reaction was cooled to -78oC again and 3-methylthio-1,2,4-triazine
(1.0g, 7.87mmol) was added. The resulting solution was stirred at - 78oC for 30min
before tributyltin chloride (2.1ml, 7.87mmol) was added. The reaction was kept at
-78oC for 1hr, then quenched with water. The THF solvent was removed on rotarory evaporator
and the remaining solution was extracted with ethylacetate. The organic layer was
dried over MgSO4, filtered and the filtrate was concentrated. The residue was chromatographed
to afford 96mg of 3-methylthio-6-tributyltin-1,2,4-triazine.
1H NMR (300Hz, CHCl3): 8.83 (s, 1H); 2.62 ( s, 3H); 2.04 - 0.79 (m, 27H). LC/MS: (ES+)
M/Z (M+H)+ = 418, RT = 2.29min.
Intermediate 15
[0371]

[0372] To a mixture of
5q (50 mg, 105 µmol) and Pd(PPh
3)
4 (25 mg, 21 µmol) was added 1,4-dioxane (1 ml) and
vinyl tributylstannane (50 mg, 158 µmol). The reaction mixture was heated in a sealed tube at 145°C for
3 hours. After cooling to ambient temperature, the reaction mixture was added MeOH
(4 ml) and then filtered. The filtrate was purified by preparative reverse phase HPLC
to give the TFA salt of
Intermediate 13 using the method: Start %B = 30, Final %B = 75, Gradient time = 20 min, Flow Rate
= 25 ml/min, Column : YMC C18 5um 20 x 100mm, Fraction Collection: 7.92 - 8.58 min.
1H NMR: (CD
3OD) δ 8.61 (s, 1H), 8.37 (s, 1H), 7.47 (b s, 5H), 7.31 (dd,
J = 17.3, 11.3, 1H), 6.50 (d,
J = 17.3, 1H), 5.97 (d,
J = 11.3, 1H), 3.97 - 3.38 (b m, 8H);
LC/MS: (ES+) m/z (M+H)
+= 423, 425; HPLC R
t = 1.887.
Intermediate 14
[0373]

[0374] To a mixture of
intermediate 5q (30 mg, 63 µmol) and Pd(PPh
3)
4 (20 mg, 17 µmol) was added 1,4-dioxane (1 ml) and 1-tributylstannyl propyne (40 mg,
122 µmol). The reaction mixture was heated in a sealed tube at 145°C for 2 hours.
After cooling to ambient temperature, the reaction mixture was added MeOH (4 ml) and
then filtered. The filtrate was purified by preparative reverse phase HPLC to give
the TFA salt of
intermediate 14 (1-(4-Benzoyl-pipemin-1-yl)-2-(4-chloro-7-prop-1-ynyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-ethane-1,2-dione)
using the method: Start %B = 20, Final %B = 80, Gradient time = 20 min, Flow Rate
= 25 ml/min, Column : YMC C 18 5um 20 x 100mm, Fraction Collection: 8.74 - 9.00 min.
1H NMR: (CD
3OD) δ 8.47 (s, 1H), 8.27 (s, 1H), 7.46 (b s, 5H), 3.82 - 3.34 (b m, 8H), 2.26 (s,
3H);
LC/MS: (ES+) m/z(M+H)
+=435,437; HPLC R
t = 2.123.
Intermediate 15
[0375]

[0376] To a solution of intermediate 5q (50 mg, 0.11 mmol) in DMF (1 ml) was added CuCN
(30 mg, 0.335 mmol). The reaction mixture was heated at 170°C for 30 min. After cooling
to ambient temperature, the reaction mixture was diluted with MeOH (15 ml), filtered
under gravity, and the filtrate evaporated
in vacuo to afforded a brownish residue. To the residue in EtOH (3 ml) at ambient temperature
was bubbled hydrogen chloride gas for 10 minutes to give a yellow solution, which
was purified by preparative reverse phase HPLC using the method: Start %B = 15, Final
%B = 85, Gradient time =15 min, Flow Rate = 40 ml/min, Column : TERRA C18 5 um 30
x 100 mm, Fraction Collection: 10.40 - 10.85 min;
1H NMR: (CD
3OD) 8.35 (s, 1H), 8.33 (s, 1H), 7.42 (b s, 5H), 3.95 - 3.41 (b m, 8H);
LC/MS: (ES+) m/z (M+H)
+= 440, 442; HPLC R
t = 1.820.
Intermediate 16
[0377]

Preparation of intermediate 16:
[0378] To a suspension of
intermediate 15 (6 mg, 13 µmol) in a mixture of AcOH (0.5 ml) and Ac
2O (1.0 ml) at 0°C was charged with sodium nitrite (17 mg, 246 µmol). The reaction
mixture was stirred at 0°C for 30 min. and then at ambient temperature for 1 hour.
After addition of MeOH (4 ml), the reaction mixture was purified by preparative reverse
phase HPLC to give the TFA solvate of the title compound using the method: Start %B
= 15, Final %B = 80, Gradient time = 15 min, Flow Rate = 25 ml/min, Column : YMC C18
5um 20 x 100mm, Fraction Collection: 9.48 - 10.03 min.
1H NMR: (DMSO-
d6) □ 12.76 (s, 1H), 8.48 (s, 1H), 8.32 (d,
J = 3.0, 1H), 7.44 (b s, 5H), 3.97 - 3.47 (b m, overlapping with water peak, 8H);
LC/MS: (ES+) m/z (M+H)
+= 441, 443; HPLC R
t = 1.530.
Ref: Amide hydrolysis:
Evans, D. A.; Carter, P. H.; Dinsmore, C. J.; Barrow, J. C.; Katz, J. L.; Kung, D.
W. Tetrahedron Lett. 1997, 38, 4535 and references cited therein.
Preparation of Compounds of Formula I
EXAMPLE 1
[0379]

[0380] Typical procedure for coupling azaindole with aromatic boron reagent (An example of
the general procedure described below for examples 2-14): Preparation of 1-benzoyl-3-(R)-methyl-4-[(7-(4-fluorophenyl)-6-azaindol-3-yl)-oxoacetyl]-piperazine
is an example of Step E as described in Scheme 15. To a sealed tube, 1-(benzoyl)-3-(R)-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine,
Intermediate 5a, (20 mg, 0.049 mmol), 4-fluorophenylboronic acid, Intermediate 14a-9,
(8.2 mg, 0.059 mmol), Pd(Ph
3P)
4 (5 mg) and K
2CO
3 (20 mg, 0.14 mmol) were combined in 1.5 mL of DMF and 1.5 mL of water. The reaction
was heated at 110-120 °C for 10 h. After the mixture cooled down to rt, it was poured
into 20 mL of water. The solution was extracted with EtOAc (4 x 20 mL). The combined
extract was concentrated to give a residue which was purified using a Shimadzu automated
preparative HPLC System to give compound 1-benzoyl-3-(R)-methyl-4-[(7-(4-fluorophenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine
(1.8 mg, 7.9%). MS
m/
z: (M+H)
+ Calc'd forC
27H
24FN
4O
3: 471.18; found 471.08. HPLC retention time: 1.12 minutes (column A).
EXAMPLES 2-14
[0381] Examples 2-14 were prepared according to the following general method in a manner
analogous to the preparation of Example 1.
[0382] Typical procedure for coupling azaindole with aromatic boron reagent: To a sealed tube, an appropriately substituted azaindole intermediate (0.049 mmol),
an appropriate boronic acid derivative (0.059 mmol), Pd(Ph
3P)
4 (5 mg) and K
2CO
3 (20 mg, 0.14 mmol) were combined in 1.5 mL of DMF and 1.5 mL of water. The reaction
was heated at 110-120 °C for 10 h. After the mixture cooled down to rt, it was poured
into 20 mL of water. The solution was extracted with EtOAc (4 x 20 mL). The combined
extract was concentrated
in vacuo to give a residue which was purified using a Shimadzu automated preparative HPLC
System to provide the desired compound.
EXAMPLE 2
[0383]

[0384] Example 2, was prepared according to the general method described above starting
from Intermediate 5g and 4-chlorophenyl boronic acid, Intermediate 14a-10, to provide
1-benzoyl-4-[(7-(4-chlorophenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/
z: (M+H)
+ Calc'd forC
27H
24FN
4O
3: 473.14; found 473.13. HPLC retention time: 1.43 minutes (column B).
EXAMPLE 3
[0385]

[0386] Example 3, was prepared according to the general method described above starting
from Intermediate 5a and 3-amino-4-methylphenyl boronic acid, Intermediate 14a-11,
to provide 1-benzoyl-3-®-methyl-4-[(7-(3-amino-4-methylphenyl)-6-azaindol-3-yl)-oxoacetyl]
piperazine. MS
m/z: (M+H)
+ Calc'd forC
27H
24ClN
4O
3: 482.22; found 482.25. HPLC retention time: 1.35 minutes (column B).
EXAMPLE 4
[0387]

[0388] Example 4, was prepared according to the general method described above starting
from Intermediate 5g and 4-hydroxycarbonylphenyl boronic acid, Intermediate 14a-12,
to provide 1-benzoyl-4-[(7-(4-carboxy-phenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/z: (M+H)
+ Calc'd forC
27H
24ClN
4O
3: 483.17; found 483.10. HPLC retention time: 1.00 minutes (column A).
EXAMPLE 5
[0389]

[0390] Example 5, was prepared according to the general method described above from 1-benzoyl-3-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine
and 3,4-methylenedioxyphenyl boronic acid, Intermediate 14a-13, to provide 1-benzoyl-3-methyl-4-[(7-(3,4-methylenedioxyphenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/z: (M+H)
+ Calc'd forC
28H
25N
4O
5: 497.18; found 497.03. HPLC retention time: 1.41 minutes (column B).
EXAMPLE 6
[0391]

[0392] Example 6, was prepared according to the general method described above starting
from Intermediate 5a and furan-2-yl boronic acid to provide 1-benzoyl-3-®-methyl-4-[(7-(furan-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd forC
25H
23N
4O
4: 443.17; found 443.12. HPLC retention time: 1.20 minutes (column A).
EXAMPLE 7
[0393]

[0394] Example 7, was prepared according to the general method described above starting
from Intermediate 5g and furan-2-yl boronic acid to provide 1-benzoyl-4-[(7-(furan-2-yl)-6-azaindol-3-yl)-oxoacetyl]
piperazine MS
m/z: (M+H)
+ Calc'd forC
24H
21N
4O
4: 429.16; found 428.98. HPLC retention time: 1.36 minutes (column A).
EXAMPLE 8
[0395]

[0396] Example 8, was prepared according to the general method described above starting
from Intermediate 5g and benzofuran-2-yl boronic acid to provide 1-benzoyl-4-[(7-(benzofuran-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
MS
m/z: (M+H)
+ Calc'd forC
28H
23N
4O
4: 479.17; found 479.09. HPLC retention time: 1.67 minutes (column B).
EXAMPLE 9
[0397]

[0398] Example 9, was prepared according to the general method described above starting
from Intermediate 5a and thien-2-yl boronic acid to provide 1-(benzoyl)-3-®-methyl-4-[(7-(thien-2-yl)-6-azaindol-3-yl)-oxoacetyl)piperazine
MS
m/z: (M+H)
+ Calc'd forC
25H
23N
4O
3S: 459.15; found 459.10. HPLC retention time: 1.20 minutes (column A).
EXAMPLE 10
[0399]

[0400] Example 10, was prepared according to the general method described above starting
from Intermediate 5g and pyridin-4-yl boronic acid to provide 1-(benzoyl)-4-[(7-(pyridin-4-yl)-6-azaindol-3-ylroxoacetyl]piperazine
MS
m/z: (M+H)
+ Calc'd forC
25H
22N
5O
3: 440.17; found 440.10. HPLC retention time: 0.97 minutes (column A).
EXAMPLE 11
[0401]

[0402] Example 11, was prepared according to the general method described above starting
from Intermediate 5g and quinolin-8-yl boronic acid, Intermediate 14a-14, to provide
1-benzoyl-4-[(7-(quinolin-8-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MS
m/z: (M+H)
+ Calc'd forC
25H
22N
5O
3: 490.19; found 490.09. HPLC retention time: 1.34 minutes (column B).
EXAMPLE 12
[0403]

[0404] Example 12, was prepared according to the general method described above starting
from Intermediate 5a and 2,4-dimethoxypyrimidin-5-yl boronic acid, Intermediate 14a-4,
to provide 1-benzoyl-3-®-methyl-4-[(7-(2,4-dimethoxy-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
MS
m/z: (M+H)
+ Calc'd for C
27H
27N
6O
5: 515.20; found 515.28. HPLC retention time: 1.17 minutes (column B).
EXAMPLE 13
[0405]

[0406] Example 13, was prepared according to the general method described above starting
from Intermediate 5b and 2,4-dimethoxypyrimidin-5-yl boronic acid, Intermediate 14a-4,
to provide 1-benzoyl-4-[(4-methoxy-7-(2,4-dimethoxy-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
1H NMR (500 MHz, CD
3OD) δ 8.71 (s, 1H), 8.64 (s, 1H), 8.21 (s, 1H), 7.48 (s, 5H), 4.15 (s, 3H), 4.13 (s,
3H), 3.84 (s, 3H), 3.64 - 3.34 (m, 8H). MS
m/z: (M+H)
+ Calc'd for C
29H
35N
6O
6: 531.20; found 531.26. HPLC retention time: 1.09 minutes (column A).
EXAMPLE 14
[0407]

[0408] Example 14, was prepared according to the general method described above starting
from Intermediate 5b and pyridin-4-yl boronic acid to provide 1-benzoyl-4-[(4-methoxy-7-(pyridin-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
MS
m/z: (M+H)
+ Calc'd for C
26H
24N
5O
4: 470.18; found 470.32. HPLC retention time: 1.02 minutes (column A).
EXAMPLE 15
[0409]

[0410] Typical procedure for coupling azaindole with aromatic tin reagent (An example of
the general procedure described below for examples 16-53): Preparation of Example 15, 1-benzoyl-4-[(4-methoxy-7-(2-(1,1-dimethylethylaminocarbonyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
is an example of Step E as described in Scheme 15. To a sealed tube, 1-benzoyl-4-[(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetyl]piperazine,
Intermediate 5b, (20 mg), 2-(1,1-dimethylethylaminocarbonyl)-5-tributylstannyl-pyrazine
(1.2 equivalents, 27 mg.) and Pd(Ph
3P)
4 (1 mg) were combined in 1.5 mL of dioxane. The reaction was heated at 110-120 °C
for 10 h. After the mixture cooled down to room temperature, it was poured into 5
mL of water. The solution was extracted with EtOAc (4 x 5 mL). The combined extract
was concentrated
in vacuo to give a residue which was purified using a Shimadzu automated preparative HPLC
System to give compound 1-benzoyl-4-[(4-methoxy-7-(2-(1,1-dimethylethylaminocarbonyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
(1 mg); MS
m/z: (M+H)
+ Calc'd for C
30H
32N
7O
5: 570.25; found 570.43. HPLC retention time: 1.83 minutes (column B).
EXAMPLES 16-54
[0411] Examples 16-54 were prepared according to the following general procedure by a method
analogous to the method described for the preparation of Example 15.
[0412] Typical procedure for coupling azaindole with aromatic tin reagent: To a sealed tube, an appropriate azaindole (0.049 mmol), an appropriate stannane
(0.059 mmol) and Pd(Ph
3P)
4 (1 mg) were combined in 1.5 mL of dioxane. The reaction was heated at 110-120 °C
for 10 h. After the mixture cooled down to rt, it was poured into 5 mL of water. The
solution was extracted with EtOAc (4 x 5 mL). The combined extract was concentrated
to give a residue which was purified using a Shimadzu automated preparative HPLC System
to provide the desired compound.
EXAMPLE 16
[0413]

[0414] Example 16, was prepared according to the general method described above starting
from Intermediate 5a and pyrimidin-5-yl tributyltin, Intermediate 14-9, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd forC
25H
23N
6O
3: 455.18; found 455.17. HPLC retention time: 1.33 minutes (column B).
EXAMPLE 17
[0415]

[0416] Example 17, was prepared according to the general method described above starting
from Intermediate 5g and pyrimidin-5-yl tributyltin, Intermediate 14-9, to provide
1-benzoyl-4-[(7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MS
m/
z: (M+H)
+ Calc'd forC
25H
23N
6O
3: 441.17; found 441.07. HPLC retention time: 1.30 minutes (column B).
EXAMPLE 18
[0417]

[0418] Example 18, was prepared according to the general method described above starting
from Intermediate 5a and pyridin-3-yl tributyltin, Intermediate 14a-2, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(pyridin-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
MS
m/z: (M+H)
+ Calc'd forC
26H
24N
5O
3: 454.19; found 454.17. HPLC retention time: 1.11 minutes (column A).
EXAMPLE 19
[0419]

[0420] Example 19, was prepared according to the general method described above starting
from Intermediate 5g and pyridin-2-yl tributyltin, Intermediate 14a-19, to provide
1-benzoyl-4-[(7-(pyridin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MS
m/z: (M+H)
+ Calc'd forC
25H
22N
5O
3: 440.17; found 440.07. HPLC retention time: 1.40 minutes (column B).
EXAMPLE 20
[0421]

[0422] Example 20, was prepared according to the general method described above starting
from Intermediate 5a and thiazol-2-yl tributyltin, Intermediate 14a-21, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(thiazol-2-yl)-6-azaindol-3-yl)oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd forC
24H
22N
5O
3S: 460.14; found 460.15. HPLC retention time: 1.48 minutes (column B).
EXAMPLE 21
[0423]

[0424] Example 21, was prepared according to the general method described above starting
from Intermediate 5g and thiazol-2-yl tributyltin, Intermediate 14a-21, to provide
1-benzoyl-4-[(7-(thiazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS
m/z: (M+H)
+ Calc'd forC
23H
20N
5O
3S: 446.13; found 446.03. HPLC retention time: 1.44 minutes (column B).
EXAMPLE 22
[0425]

[0426] Example 22, was prepared according to the general method described above starting
from Intermediate 5b and 1-methylpyrazol-3-yl tributyltin, to provide 1-benzoyl-4-[(4-methoxy-7-(1-methyl-pyrazol-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
25H
25N
6O
4: 473.19; found 473.28. HPLC retention time: 1.18 minutes (column B).
EXAMPLE 23
[0427]

[0428] Example 23, was prepared according to the general method described above starting
from Intermediate 5b and Intermeidiate 14-9 to provide 1-benzoyl-4-[(4-methoxy-7-(pyridazin-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
25H
23N
6O
4: 471.18; found 471.26. HPLC retention time: 1.20 minutes (column B).
EXAMPLE 24
[0429]

[0430] Example 24, was prepared according to the general method described above starting
from Intermediate 5b and 2-aminopyrimidin-5-yl tributyltin, to provide 1-benzoyl-4-[(4-methoxy-7-(2-amino-pyrimidin-5-yl))-6-azaindol-3-yl)-oxoacetyl]piperazine
MS
m/z: (M+H)
+ Calc'd for for C
23H
24N
7O
4: 486.19: found 486.24. HPLC retention time: 1.19 minutes (column A).
EXAMPLE 25
[0431]

[0432] Example 25, was prepared according to the general method described above starting
from Intermediate 5b and pyridin-3-yl tributyltin, Intermediate 14a-2, to provide
1-benzoyl-4-[(4-methoxy-7-(pyridin-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS
m/z: (M+H)
+ Calc'd for C
26H
24N
5O
4: 470.18; found 470.19. HPLC retention time: 1.04 minutes (column A).
EXAMPLE 26
[0433]

[0434] Example 26, was prepared according to the general method described above starting
from Intermediate 5b and 2-aminopyrazin-5-yl trimethyltin, Intermediate 14-28, to
provide 1-benzoyl-4-[(4-methoxy-7-(2-amino-pyrazin-5-yl))-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
25H
24N
7O
4: 486.19; found 470.19. HPLC retention time: 1.13 minutes (column B).
EXAMPLE 27
[0435]

[0436] Example 27, was prepared according to the general method described above starting
from Intermediate 5b and 1-methylimidazol-2-yl trimethyltin, Intermediate 14-5, to
provide 1-benzoyl-4-[(4-methoxy-7-(1-methyl-imidazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
25H
25N
6O
4: 473.18; found 473.27. HPLC retention time: 1.07 minutes (column B).
EXAMPLE 28
[0437]

[0438] Example 28, was prepared according to the general method described above starting
from Intermediate 5b and 1-methylpyrrol-2-yl tributyltin, Intermediate 14a-15, to
provide 1-benzoyl-4-[(4-methoxy-7-(1-methyl-pyrrol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
26H
26N
5O
4: 472.20; found 470.26. HPLC retention time: 1.11 minutes (column A).
EXAMPLE 29
[0439]

[0440] Example 29, was prepared according to the general method described above starting
from Intermediate 5i and 1-methylpyrazol-3-yl tributyltin, to provide 1-benzoyl-4-[(4-fluoro-7-(1-methyl-pyrazol-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
24H
22FN
6O
3: 461.17; found 461.24. HPLC retention time: 1.36 minutes (column A).
EXAMPLE 30
[0441]

[0442] Example 30, was prepared according to the general method described above starting
from Intermediate 5i and pyridazin-4-yl tributyltin, Intermediate 14-8, to provide
1-benzoyl-4-[(4-fluoro-7-(pyridazin-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
1H NMR (500 MHz, CD
3OD) δ 9.72 (s, 1H), 9.39 (s, 1H), 8.42 (m, 2H), 8.22 (s, 1H), 7.47 (s, 5H), 3.84 -
3.38 (m, 8H). MS
m/z: (M+H)
+ Calc'd for C
24H
20FN
6O
3: 459.16; found 459.25. HPLC retention time: 1.26 minutes (column A).
EXAMPLE 32
[0443]

[0444] Example 32, was prepared according to the general method described above starting
from Intermediate 5b and pyrazin-2-yl tributyltin, Intermediate 14a-1, to provide
1-benzoyl-4-[(4-methoxy-7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS
m/z: (M+H)
+ Calc'd for C
25H
23N
6O
3: 471.18; found 471.17. HPLC retention time: 1.35 minutes (column A).
EXAMPLE 33
[0445]

[0446] Example 33, was prepared according to the general method described above starting
from Intermediate 5a and pyrazin-2-yl tributyltin, Intermediate 14a-1, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
25H
23N
6O
3: 455.18; found 455.26. HPLC retention time: 1.46 minutes (column A).
EXAMPLE 34
[0447]

[0448] Example 34, was prepared according to the general method described above starting
from Intermediate 5g and pyrazin-2-yl tributyltin, Intermediate 14a-1, to provide
1-benzoyl-4-[(7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS
m/z: (M+H)
+ Calc'd for C
24H
21N
6O
3: 441.17; found 441.22. HPLC retention time: 1.22 minutes (column A).
EXAMPLE 35
[0449]

[0450] Example 35, was prepared according to the general method described above starting
from Intermediate 5b and thiazol-2-yl tributyltin, Intermediate 14a-21, to provide
1-(benzoyl)-4-[(4-methoxy-7-(thiazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
24H
22N
5O
3S: 476.14; found 476.20. HPLC retention time: 1.25 minutes (column B).
EXAMPLE 36
[0451]

[0452] Example 36, was prepared according to the general method described above starting
from Intermediate 5b and pyridin-2-yl tributyltin, Intermediate 14a-19, to provide
1-benzoyl-4-[(4-methoxy-7-(pyridin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS
m/z: (M+H)
+ Calc'd for C
26H
24N
5O
4: 470.18; found 470.17. HPLC retention time: 1.04 minutes (column A).
EXAMPLE 37
[0453]

[0454] Example 37, was prepared according to the general method described above starting
from Intermediate 5j and thiazol-2-yl tributyltin, Intermediate 14a-21, to provide
1-benzoyl-3-(R)-methyl-4-[(4-fluoro-7-(thiazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
24H
21FN
5O
3S, 478.13; found 478.13. HPLC retention time: 1.34 minutes (column A).
EXAMPLE 38
[0455]

[0456] Example 38, was prepared according to the general method described above starting
from Intermediate 5i and pyrazol-3-yl tributyltin, to provide 1-benzoyl-4-[(4-fluoro-7-(pyrazol-3
yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MS
m/z: (M+H)
+ Calc'd for C
23H
20FN
6O
3: 447.16; found 447.15. HPLC retention time: 1.26 minutes (column A).
EXAMPLE 39
[0457]

[0458] Example 39, was prepared according to the general method described above starting
from Intermediate 5b and pyrazol-3-yl tributyltin, to provide 1-benzoyl-4-[(4-methoxy-7-(pyrazol-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
24H
23N
6O
4: 459.18; found 459.21. HPLC retention time: 1.11 minutes (column A).
EXAMPLE 40
[0459]

[0460] Example 40, was prepared according to the general method described above starting
from Intermediate 5b and pyrimidin-5-yl tributyltin, Intermediate 14-9, to provide
1-benzoyl-4-[(4-methoxy-7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MS
m/z: (M+H)
+ Calc'd for C
25H
23N
6O
4: 471.18; found 471.20. HPLC retention time: 1.61 minutes (column A).
EXAMPLE 41
[0461]

[0462] Example 41, was prepared according to the general method described above starting
from Intermediate 5j and pyrimidin-5-yl tributyltin, Intermediate 14-9, to provide
1-benzoyl-3-(R)-methyl-4-[(4-fluoro-7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
H NMR (500 MHz, CD
3OD) δ 9.26 (m, 3H), 8.39 (m, 2H), 7.56 (m, 5H), 4.72 - 3.12 (m, 7H), 1.40 - 0.91 (m,
3H). MS
m/z: (M+H)
+ Calc'd for C
25H
22FN
6O
3: 473.17; found 473.17. HPLC retention time: 1.34 minutes (column A).
EXAMPLE 42
[0463]

[0464] Example 42, was prepared according to the general method described above starting
from Intermediate 5i and pyrimidin-5-yl tributyltin, Intermediate 14-9, to provide
1-benzoyl-4-[(4-fluoro-7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS
m/z: (M+H)
+ Calc'd for C
24H
20FN
6O
3: 459.16; found 459.14. HPLC retention time: 1.28 minutes (column A).
Example 43
[0465]

[0466] Example 43, (R)-1-(benzoyl)-3-methyl-4-[(7-(2,4-dimethoxy-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
MS
m/z: (M+H)
+ Calc'd for C
27H
27N
6O
5: 515.20; found 515.28. HPLC retention time: 1.17 minutes (column B).
EXAMPLE 44
[0467]

[0468] Example 44, was prepared according to the general method described above starting
from Intermediate 5a and 2,3-dichloropyrazin-5-yl tributyltin, Intermediate 14-66,
to provide 1-benzoyl-3-(R)-methyl-4-[(7-(2,3-dichloro-pyrazin-5-yl) -6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+Na)
+ Calc'd for C
25H
20Cl
2NaN
6O
3: 545.09; found 545.29. PLC retention time: 1.87 minutes (column B).
EXAMPLE 45
[0469]

[0470] Example 45, was prepared according to the general method described above starting
from Intermediate 5b and 2-ethoxythiazol-5-yl tributyltin, Intermediate 14-71, to
provide 1-benzoyl-4-[(4-methoxy-7-(2-ethoxy-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
26H
26N
5O
5S: 520.17; found 520.24. HPLC retention time: 1.32 minutes (column A).
EXAMPLE 46
[0471]

[0472] Example 46, was prepared according to the general method described above starting
from Intermediate 5b and the 2-amino-pyrazin-6-yl stannane, Intermediate 14-68, to
provide 1-benzoyl-4-[(4-methoxy-7-(2-amino-pyrazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
25H
24N
7O
4: 486.19; found 486.31. HPLC retention time: 1.22 minutes (column B).
EXAMPLE 47
[0473]

[0474] Example 47, was prepared according to the general method described above starting
from Intermediate 5b and 2-methylsulfonylamino-5-(tri-n-butylstannyl)pyrazine, Intermediate
14-69, to provide 1-benzoyl-4-[(7-(2-methylsulfonylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl)piperazine
MS
m/z: (M+H)
+ Calc'd for C
26H
26N
7O
6S: 564.17; found 564.21. HPLC retention time: 1.24 minutes (column A).
EXAMPLE 48
[0475]

[0476] Example 48, was prepared according to the general method described above starting
from Intermediate 5b and 2,4-dimethoxy-1,3,5-triazin-6-yl tributyltin, Intermediate
14-70, to provide 1-benzoyl-4-[(7-(2,4-dimethoxy-1,3,5-triazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
26H
26N
7O
6: 532.19; found 532.12. HPLC retention time: 1.28 minutes (column A).
EXAMPLE 49
[0477]

[0478] Example 49, was prepared according to the general method described above starting
from Intermediate 5b and pyrimidin-2-yl tributyltin, Intermediate 14-67, to provide
1-benzoyl-4-[(4-methoxy-7-(pyrimidin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
25H
23N
6O
4: 471.18; found 471.29. HPLC retention time: 1.21 minutes (column A).
EXAMPLE 50
[0479]

[0480] Example 50, was prepared from1-(pyridin-2-yl)-4-[(4-methoxy-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine
and thiazol-2-yl tributyltin, Intermediate 14a-21, according to the general method
above to provide 1-(pyridin-2-yl)-4-[(4-methoxy-7-(thiazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
MS
m/z: (M+H)
+ Calc'd for C
24H
25N
6O
4S: 477.13; found 477.22. HPLC retention time: 0.98 minutes (column A).
EXAMPLE 51
[0481]

[0482] Example 51, was prepared according to the general method described above starting
from Intermediate 5d and pyrimidin-5-yl tributyltin, Intermediate 14-9, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(pyrimidin-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/z: (M+H)
+ Calc'd for C
25H
23N
6O
3: 455.18; found 455.16. HPLC retention time: 0.98 minutes (column A).
EXAMPLE 52
[0483]

[0484] Example 52, was prepared according to the general method described above starting
from Intermediate 5d and pyrimidin-2-yl tributyltin, Intermediate 14a-1, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(pyrazin-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine;
MS m/z: (M+H)
+ Calc'd for C
25H
23N
6O
3: 455.18; found 455.16. HPLC retention time: 1.09 minutes (column A).
EXAMPLE 53
[0485]

[0486] Example 53, was prepared according to the general method described above starting
from Intermediate 5d and thiazol-2-yl tributyltin, Intermediate 14a-21, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(thiazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/
z: (M+H)
+ Calc'd for C
24H
22N
5O
3S: 460.14; found 460.26. HPLC retention time: 1.02 minutes (column A).
EXAMPLE 54
[0487]

[0488] Example 54, was prepared according to the general method described above starting
from Intermediate 5d and 2-ethoxythiazol-5-yl tributyltin, Intermediate 14-71, to
provide 1-benzoyl-3-(R)-methyl-4-[(7-(2-ethoxy-thiazol-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/
z: (M+H)
+ Calc'd for C
26H
26NO
4S: 504.17; found 4504.18. HPLC retention time: 1.26 minutes (column A).
EXAMPLE 55
[0489]

[0490] The compound of Example 15, 1-benzoyl-4-[(4-methoxy-7-(2-(1,1-dimethylethylaminocarbonyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
(20 mg) was dissolved in 1 drop of concentrated sulfuric acid. After 30 minutes, the
mixture was diluted with 2 mL of methanol. The resulting solution was injected into
a Shimadzu automated preparative HPLC System and the HPLC purification afforded the
compound of Example 55, 1-benzoyl-4-[(4-methoxy-7-(2-aminocarbonyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
(1 mg); MS
m/
z: (M+H)
+ Calc'd for C
26H
24N
7O
5: 514.78; found 514.22. HPLC retention time: 1.44 minutes (column B).
EXAMPLE 56
[0491]

[0492] An excess of NH
4Cl (27mg) was added into a solution of 1-(benzoyl)-3-(R)-methyl-4-[(6-cyano-7-azaindol-3-yl)-oxoacetyl]piperazine
(20 mg) and NaN
3 (16 mg) in DMF. The reaction was heated to reflux for 12 h. After cooling down, the
mixture was concentrated under reduced pressure and the residue was purified using
Shimadzu automated preparative HPLC System to give 1-benzoyl-3-(R)-methyl-4-[(6-(tetrazol-l-yl)-7-azaindol-3-yl)-oxoacetyl]piperazine
(6.3mg). MS
m/
z: (M+H)
+ Calc'd for C
22H
21,N
8O
3: 445.17; Found 3445.16. HPLC retention time: 1.42 minutes (column B); Column B: PHX-LUNA
C18 4.6 x 30 mm.
EXAMPLE 57
[0493]

[0494] Preparation of 1-benzoyl-3-(R)-methyl-4-[(7-(methoxymethylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine:
A mixture of Intermediate 13 (267 mg), N,O-dimethylhydroxylamine hydrogen chloride
(248 mg), carbon tetrabromide (844 mg), pyridine (202 mg) and triphenylphosphine (668
mg) in dichloromethane (10 mL) was stirred at room temperature for 10 hours. After
solvent was removed under vaccum, the residue was purified by using silica gel chromatography
to afford 1-(benzoyl)-3-(R)-methyl-4-[(7-(methoxymethylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine
(56 mg); MS m/z: (M+H)
+ Calc'd for C
24H
26N
5O
5: 464.19; found 464.25. HPLC retention time: 1.02 minutes (column A).
EXAMPLE 58
[0495]

[0496] Example 58 was prepared according to the same procedure used in preparing Example
57 with the exception of using Intermediate 11 as a starting material instead of Intermediate
13. The procedure provided 1-benzoyl-3-(R)-methyl-4-[(5-chloro-(7-(methoxymethylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/
z: (M+H)
+ Calc'd for C
24H
25ClNO
5: 498.15; found 498.12. HPLC retention time: 1.39 minutes (column A).
General procedure A to prepare CO-NR1R2 fromCOOH
EXAMPLE 59
[0497]

[0498] Preparation of 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(methylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine:
A mixture of Intermediate 11 (25 mg), methylamine (2M in THF, 0.08 mL), EDC (26 mg),
HOBT (11.2 mg) and diisopropylethylamine (43 mg) in tetrahydrofuran (5 mL) was stirred
at room temperature for 10 hours. After the solvent was removed under vaccum, the
residue was purified by using silica gel chromatography to afford 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(methylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine
(13.6 mg); MS
m/
z: (M+H)
+ Calc'd for C
23H
23ClN
5O
4: 468.14; found 468.03. HPLC retention time: 1.33 minutes (column A).
[0499] This general produre A is applied to prepare examples 94 and 135:
Example 94
[0500]

[0501] Example 94,1-benzoyl-4-[(4-methoxy-7-(2-methylaminocarbonyl-furan-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ8.37 (s, 1H), 8.06 (s, 1H), 7.48 - 7.26 (m, 7H), 4.08 (s, 3H), 3.83 - 3.44 (m,
8H), 2.96 (s, 3H). MS m/z: (M+H)
+ Calc'd for C
29H
26N
5O
6: 516.19; found 516.14. HPLC retention time: 1.35 minutes (column A).
Example 135
[0502]

[0503] Example 135, (R)-1-benzoyl-3-methyl-4-[(7-(4-trifluoromethylbenzylamino) carbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (N4+H)
+ Calc'd for C
30H
27F
3N
5O
4: 578.20; found 578.39. HPLC retention time: 1.47 minutes (column G).
General procedure B to prepare CO-NR1R2 fromCOOH
[0504]

Preparation of Example 136, (R)-1-benzoyl-3-methyl-4-[(7-(4-methylthiazol-2-yl)aminocarbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine:
[0505] To a solution of (R)-1-benzoyl-3-methyl-4-[(7-hydroxylcarbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine
(146mg) in DMF (5ml) at room temperature was added pentafluorophenyl (70.3mg) followed
by EDC (73.23mg). The reaction mixture was stirred at room temperature for 8 hours.
The crude product was diluted with methylene chloride and was washed with water, 0.1N
HCl and brine. The organic phase was dried over MgSO4, filtered and concentrated.
The pentafluorophenyl ester was used in the following reaction without further purification.
[0506] To a stirred solution of 4-methyl-2-amino-thiazole (39.6mg) and Hunig's base (49.4mg)
in DMF (5ml) at room temperature was added a solution of pentafluorophenyl ester (1/3
of the product obtained in the previous step described above) in DMF (2 ml). The reaction
mixture was stirred at room temperature for 16 hours. The crude product was diluted
with methylene chloride and was washed with Na2C03 (sat.) and brine. The organic phase
was dried over MgSO4, filtered and concentrated. The residue was purified using. Shimadzu
automated preparative HPLC System to give (R)-1-benzoyl-3-methyl-4-[(7-(4-methylthiazol-2-yl)aminocarbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine
(3.6mg). MS
m/
z: (M+H)
+ Calc'd for C
26H
25N
6O
4S: 517.17; found 517.41. HPLC retention time: 1.25 minutes (column A).
This general produre B is applied to prepare example 137:
Example 137
[0507]

[0508] Example 137, (R)-1-benzoyl-3-methyl-4-[(7-(thiazol-2-yl)aminocarbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
6O
4S: 503.15; found 503.29. HPLC retention time: 1.33 minutes (column A).
EXAMPLE 60
[0509]

[0510] Preparation of 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(imidazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine:
A mixture of Intermediate 10 (34 mg), glyoxal (40% in water, 0.2 mL) and ammonia acetate
(139 mg) in methanol was heated up to reflux for 10 hours. After cooling down, the
mixture was concentrated under reduced pressure and the residue was purified using
Shimadzu automated preparative HPLC System to provide 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(imidazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine
(1.8 mg); MS
m/
z: (M+H)
+ Calc'd for C
24H
22ClN
6O
3: 477.14; found 477.13. HPLC retention time: 1.17 minutes (column A).
EXAMPLE 61
[0511]

[0512] Example 61 was prepared according to the same procedure used for preparing Example
60 with the exception of using methylglyoxal as a starting material instead of glyoxal
to provide1 -benzoyl-3-(R)-methyl-4-[(5-chloro-7-(4-methyl-imidazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine
MS
m/
z: (M+H)
+ Calc'd for C
25H
24ClN
6O
3: 491.16; found 491.13. HPLC retention time: 1.26 minutes (column A).
EXAMPLE 62
[0513]

[0514] Example 62 was prepared according to the same procedure used for preparing Example
60 with the exception of using dimethylglyoxal as a starting material instead of glyoxal
to provide 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(4,5-dimethyl-imidazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine;
MS
m/
z: (M+H)
+ Calc'd for C
26H
26ClN
6O
3: 505.18; found 505.10. HPLC retention time: 1.24 minutes (column A).
EXAMPLE 63
[0515]

[0516] Preparation of 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(oxazol-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine:
A mixture of Intermediate 10 (27.6 mg), tosylmethyl isocyanide (12.3 mg) and K
2CO
3 (8.7 mg) in MeOH was heated up to reflux for 10 hours. After cooling down, the mixture
was concentrated under reduced pressure and the residue was purified using Shimadzu
automated preparative HPLC System to provide 1-(benzoyl)-3-(R)-methyl-4-[(5-chloro-7-(oxazol-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine
(17.7 mg); MS
m/
z: (M+H)
+ Calc'd for C
24H
21 ClN
5O
4: 478.13; found 478.03. HPLC retention time: 1.48 minutes (column A).
EXAMPLE 64
[0517]

[0518] Step 1: Preparation of I-64, 1-benzoyl-3-(R)-methyl-4-[(7-(2-propynyl)carbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine:
Propynyllithium (21 mg) was added to a solution of Example 52 (41 mg) in tetrahydrofuran
(5 ml) at -78°C. The reaction was quenched with methanol at -25°C in 2 hours. After
solvents were removed under vaccum, the residue was carried to the further reactions
without any purification. I-64, 1-benzoyl-3-(R)-methyl-4-[(7-(2-propynyl)carbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine
MS
m/
z: (M+H)
+ Calc'd for C
25H
22ClN
4O
4: 477.13; found 477.17. HPLC retention time: 1.46 minutes (column A).
Step 2: Preparation of Example 64:
[0519]

[0520] Preparation of Example 64, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(3-methyl-pyrazol-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine:
A mixture of I-64 (crude product from Step 1) and hydrazine (0.22 mL) in EtOAc (2
mL) and water (2 mL) was stirred at room temperature for 24 hours. Then solvents were
removed under vaccum, and the residue was purified using Shimadzu automated preparative
HPLC System to give 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(3-methyl-pyrazol-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine
(9 mg); MS
m/
z: (M+H)
+ Calc'd for C
25H
24ClN
6O
3: 491.16; found 491.19. HPLC retention time: 1.42 minutes (column A).
EXAMPLES 65-67
[0521] The procedure for the preparation of Examples 65-67 is the same as that described
previously for the preparation of Intermediate 5a and is as follows: Potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate,
Intermediate 4c (147 mg, 0.44 mmol), an appropriate 1-benzoylpiperazine derivative
(0.44 mmol), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3
H)-one (DEPBT) (101 mg, 0.44 mol) and Hunig's Base (0.5 mL) were combined in 5 mL of
DMF. The mixture was stirred at rt for 8 h. DMF was removed via evaporation at reduced
pressure and the residue was purified using a Shimadzu automated preparative HPLC
System to give the corresponding 1-benzoyl-4-[(7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetyl]-piperazine
derivative.
EXAMPLE 65
[0522]

[0523] Example 19, 1-(benzoyl)-4-[(7-(4-methoxy)-4-azaindol-3-yl)-oxoacetyl]piperazine was
prepared from potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate and 1-(benzoyl)piperazine
according to the above general procedure. MS
m/
z: (M+H)
+ Calc'd for C
27H
25N
4O
4: 469.19; found 469.16. HPLC retention time: 1.26 minutes (column A).
EXAMPLE 66
[0524]

[0525] Example 66, 1-benzoyl-3-(S)-methyl-4-[(7-(4-methoxy)-4-azaindol-3-yl)-oxoacetyl]piperazine
was prepared from potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate and the corresponding
1-(benzoyl)-3-methylpiperazine according to the above general procedure. MS
m/
z: (M+H)
+ Calc'd for C
28H
27N
4O
4: 483.20; found 483.17. HPLC retention time: 1.30 minutes (column A).
EXAMPLE 67
[0526]

[0527] Example 67, 1-benzoyl-3-(R)-methyl-4-[(7-(4-methoxyphenyl)-4-azaindol-3-yl)oxoacetyl]piperazine
was prepared from potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate and the corresponding
1-benzoyl-3-methylpiperazine according to the above general procedure. MS
m/
z: (M+H)
+ Calc'd for C
28H
27N
4O
4: 483.20; found 483.16. HPLC retention time: 1.28 minutes (column A).
EXAMPLES 68-79 and 81
[0528] Examples 68-79 and 81 were prepared according to the same general method as previously
described for Examples 16-54.
EXAMPLE 68
[0529]

[0530] Example 68, was prepared from Intermediate 5b and the 2,4-dimethoxypyrimidin-6-yl
stannane to provide 1-benzoyl-4-[(4-methoxy-7-(2,6-dimethoxy-pyrimidin-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CDCl
3) δ 8.20 (s, 1H), 8.13 (s, 1H), 7.52 (s, 1H), 7.42 (m, 5H), 4.11 (s, 3H), 4.06 (s,
3H), 4.00 - 3.40 (m, 8H). MS
m/
z: (M+H)
+ Calc'd for C
27H
27N
6O
6: 531.20; found 531.24. HPLC retention time: 1.54 minutes (column A).
EXAMPLE 69
[0531]

[0532] Example 69, was prepared from Intermediate 5b and the 6-methoxypyridin-3-yl stannane
to provide 1-benzoyl-4-[(4-.methoxy-7-(6-methoxy-pyridin-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ 8.69 (s, 1H), 8.63 (s, 1H), 8.11 (m, 2H), 7.49 (m, 5H), 7.10 (d, 1H, J = 8.65
Hz), 4.16 (s, 3H), 4.06 (s, 3H), 4.00 - 3.40 (m, 8H). MS
m/
z: (M+H)
+ Calc'd for C
27H
26N
5O
5: 500.09; found 500.20. HPLC retention time: 1.11 minutes (column A).
EXAMPLE 70
[0533]

[0534] Example 70, was prepared from Intermediate 5b and the 2-diethylamino-thiazol-4-yl
stannane to provide 1-benzoyl-4-[(4-methoxy-7-(2-diethylamino-thiazol-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ 8.47 (s, 1H), 7.97 (m, 2H), 7.49 (m, 5H), 4.08 (s, 3H), 3.64 (m, 12H), 1.35
(m, 6H). MS
m/
z: (M+H)
+ Calc'd for C
28H
31N
6O
4S: 547.21; found 547.22. HPLC retention time: 1.35 minutes (column A).
EXAMPLE 71
[0535]

[0536] Example 71, was prepared from Intermediate 5b and the thiazol-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(thioazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, DMSO-d
6) δ 9.19 (s, 1H), 8.64 (s, 1H), 8.34 (s, 1H), 8.11 (s, 1H), 7.46 (m, 5H), 4.00 (s,
3H), 3.55 (m, 8H). MS
m/
z: (M+H)
+ Calc'd for C
24H
22N
5O
4S: 476.14; found 476.17. HPLC retention time: 1.13 minutes (column A).
EXAMPLE 72
[0537]

[0538] Example 72, was prepared from Intermediate 5b and the 2-dimethylamino-pyrazin-5-yl
stannane to provide 1-(benzoyl)-4-[(4-methoxy-7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
27H
28N
7O4: 514.22; found 514.29. HPLC retention time: 1.27 minutes (column A).
EXAMPLE 73
[0539]

[0540] Example 73, was prepared from Intermediate 5b and the furan-2-yl stannane to provide
1-(benzoyl)-4-[(4-methoxy-7-(furan-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
4O
5,: 459.17; found 459.25. HPLC retention time: 1.15 minutes (column A).
EXAMPLE 74
[0541]

[0542] Example 74, was prepared from Intermediate 5b and the oxazol-2-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(oxazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, DMSO-d
6) δ 9.19 (s, 1H), 8.64 (s, 1H), 8.34 (s, 1H), 8.11 (s, 1H), 7.46 (m, 5H), 4.00 (s,
3H), 3.55 (m, 8H). MS
m/
z: (M+H)
+ Calc'd for C
24H
22N
5O
5: 460.16; found 460.23. HPLC retention time: 1.22 minutes (column A).
EXAMPLE 75
[0543]

[0544] Example 75, was prepared from Intermediate 5b and the 6-aminopyridin-2-yl stannane
to provide 1-benzoyl-4-[(4-methoxy-7-(2-aminopyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
25N
6O
4: 485.19; found 485.24. HPLC retention time: 1.15 minutes (column A).
EXAMPLE 76
[0545]

[0546] Example 76, was prepared from Intermediate 5b and the 6-methylpyridin-2-yl stannane
to provide 1-benzoyl-4-[(4-methoxy-7-(2-methyl-pyridin-6yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
27H
26N
5O
4: 484.20; found 484.22. HPLC retention time: 1.24 minutes (column A).
EXAMPLE 77
[0547]

[0548] Example 77, was prepared from Intermediate 5b and the 6-methoxypyridin-2-yl stannane
to provide 1-benzoyl-4-[(4-methoxy-7-(2-methoxy-pyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
27H
26N
5O
5: 500.19; found 500.23. HPLC retention time: 1.26 minutes (column A).
EXAMPLE 78
[0549]

[0550] Example 78, was prepared from Intermediate 5b and the 2-acetylamino-thiazol-5-yl
stannane to provide 1-benzoyl-4-[(4-methoxy-7-(2-acetylamino-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
25N
6O
5S: 533.16; found 533.18. HPLC retention time: 1.21 minutes (column A).
EXAMPLE 79
[0551]

[0552] Example 79, was prepared from Intermediate 5b and the 2-ethylamino-pyrazin-5-yl stannane
to provide 1-benzoyl-4-[(4-methoxy-7-(2-ethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
27H
28N
7O
4: 514.22; found 514.18. HPLC retention time: 1.31 minutes (column A).
EXAMPLE 88
[0553]

[0554] Example 88, was prepared from Intermediate 5b and the 2-ethyl-thiazol-5-yl stannane
to provide 1-benzoyl-4-[(4-methoxy-7-(2-ethyl-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
26N
5O
4S: 504.17; found 514.32. HPLC retention time: 1.50 minutes (column A).
EXAMPLE 89
[0555]

[0556] Example 89, was prepared from Intermediate 5k and the 2-isobutyl-thiazol-5-yl stannane
to provide 1-benzoyl-4-[(7-(2-isobutyl-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
27H
28N
5O
3S: 502.19; found 502.26. HPLC retention time: 1.56 minutes (column E).
Example 90
[0557]

[0558] Example 90, was prepared from Intermediate 5b and the 2-isobutyl-thiazol-5-yl stannane
to provide 1-benzoyl-4-[(4-methoxy-7-(2-isobutyl-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
28H
30N
5O
4S: 532.20; found 532.27. HPLC retention time: 1.57 minutes (column E).
Example 91
[0559]

[0560] Example 91, was prepared from Intermediate 5b and the 2-(2-butyl)-thiazol-5-yl stannane
to provide 1-benzoyl-4-[(4-methoxy-7-(2-(2-butyl)-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
28H
30N
5O
4S: 532.20; found 532.27. HPLC retention time: 1.57 minutes (column E).
Example 92
[0561]

[0562] Example 92, was prepared from Intermediate 5b and the 2-(thiazol-2-yl)-thiazol-5-yl
stannane to provide 1-benzoyl-4-[(4-methoxy-7-(2-(thiazol-2-yl)-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
27H
23N
6O
4S
2: 559.12; found 559.18. HPLC retention time: 1.55 minutes (column E).
Example 93
[0563]

[0564] Example 93, was prepared from Intermediate 5b and the 2-methylthio-thiazol-5-yl stannane
to provide 1-benzoyl-4-[(4-methoxy-7-(2-methylthio-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
24N
5O
4S
2: 522.13; found 522.17. HPLC retention time: 1.45 minutes (column E).
Example 95
[0565]

[0566] Example 95, was prepared from Intermediate 5i and the pyrazin-2-yl stannane to provide
1-benzoyl-4-[(4-fluoro-7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CDCl
3) δ9.89 (s, 1H), 8.70 - 8.34 (m, 4H), 7.46 (m, 5H), 3.80 - 3.50 (m, 8H). MS
m/
z: (M+H)
+ Calc'd for C
24H
20FN
6O
3: 459.16; found 459.33. HPLC retention time: 1.46 minutes (column G).
Example 100
[0567]

[0568] Example 100, was prepared from Intermediate 5b and the 2-methylamino-3-methoxy-pyrazin-5-yl
stannane to provide 1-benzoyl-4-[(4-methoxy-7-(2-methylamino-3-methoxy-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ8.65 (s, 1H), 8.43 (s, 1H), 7.95 (s, 1H), 7.45 (m, 5H), 4.21 (s, 3H), 4.12 (s,
3H), 3.89 - 3.32 (m, 8H), 3.06 (s, 3H). MS
m/
z: (M+H)
+ Calc'd for C
27H
28N
7O
5: 530.22; found 530.19. HPLC retention time: 1.31 minutes (column A).
Example 101
[0569]

[0570] Example 101, was prepared from Intermediate 5b and the 2-amino-3-methoxy-pyrazin-5-yl
stannane to provide 1-benzoyl-4-[(4-methoxy-7-(2-amino-3-methoxy-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ8.67 (s, 1H), 8.34 (s, 1H), 7.96 (s, 1H), 7.48 (m, 5H), 4.22 (s, 3H), 4.12 (s,
3H), 3.92 - 3.32 (m, 8H). MS
m/
z: (M+H)
+ Calc'd for C
26H
26N
7O
5: 516.20; found 516.23. HPLC retention time: 1.27 minutes (column A).
Example 102
[0571]

[0572] Example 102, was prepared from Intermediate 51 and the pyrazin-2-yl stannane to provide
1-picolinoyl-4-[(4-methoxy-7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ9.59 (s, 1H), 8.79 - 7.51 (m, 8H), 4.13 (s, 3H), 3.95 -3.34 (m, 8H). MS
m/
z: (M+H)
+ Calc'd for C
24H
22N
7O
4: 472.17; found 472.25. HPLC retention time: 1.15 minutes (column A).
Example 103
[0573]

[0574] Example 103, was prepared from Intermediate 51 and the 2-dimethylamino-pyrazin-5-yl
stannane to provide 1-picolinoyl-4-[(4-methoxy-7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
27N
8O
4: 515.22; found 515.16. HPLC retention time: 1.29 minutes (column A).
Example 104
[0575]

[0576] Example 104, was prepared from Intermediate 5b and the 6-aza-benzofuran-2-yl stannane
to provide 1-benzoyl-4-[(4-methoxy-7-(6-aza-benzofuran-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CDCl
3) δ8.48 (d, 1H,
J = 8.5 Hz), 8.36 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 7.64 (d, 1H,
J = 8.55 Hz), 7.41 (m, 4H), 6.92 (s, 1H), 4.12 (s, 3H), 3.87 - 3.38 (m, 8H). MS
m/
z: (M+H)
+ Calc'd for C
28H
24N
5O
5: 510.18; found 510.33. HPLC retention time: 1.33 minutes (column A).
Example 105
[0577]

[0578] Example 105, was prepared from Intermediate 5m and the 2-dimethylamino-pyrazin-5-yl
stannane to provide (R)-1-picolinoyl-3-methyl-4-[(7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
27N
8O
3: 499.22; found 499.27. HPLC retention time: 1.17 minutes (column A).
Example 106
[0579]

[0580] Example 106, was prepared from Intermediate 5n and the 2-dimethylamino-pyrazin-5-yl
stannane to provide (S)-1-picolinoyl-3-methyl-4-[(7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ9.08 - 7.49 (m, 9H), 5.00 - 3.15 (m, 13H), 1.44 -1.27 (m, 3H). MS
m/
z: (M+H)
+ Calc'd for C
26H
27N
8O
3: 499.22; found 499.27. HPLC retention time: 1.19 minutes (column A).
Example 109
[0581]

[0582] Example 109, was prepared from Intermediate 5m and the thiazol-5-yl stannane to provide
(R)-1-picolinoyl-3-methyl-4-[(7-(thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ9.42 -7.49 (m, 9H), 4.98 - 3.14 (m, 7H), 1.43 -1.26 (m, 3H). MS
m/
z: (M+H)
+ Calc'd for C
23H
21N
6O
3S: 461.14; found 461.28. HPLC retention time: 1.11 minutes (column A).
Example 110
[0583]

[0584] Example 110, was prepared from Intermediate 5n and the thiazol-5-yl stannane to provide
(S)-1-picolinoyl-3-methyl-4-[(7-(thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine..
1H NMR (500 MHz, CD
3OD) δ9.44 - 7.48 (m, 9H), 4.98 - 3.15 (m, 7H), 1.43 -1.26 (m, 3H). MS
m/
z: (M+H)
+ Calc'd for C
23H
21N
6O
3S: 461.14; found 461.27. HPLC retention time: 1.13 minutes (column A).
Example 111
[0585]

[0586] Example 111, was prepared from Intermediate 5f and the 2-amino-pyrazin-6-yl stannane
to provide (R)-1-benzoyl-3-methyl-4-[(7-(2-amino-pyrazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ8.68 - 7.45 (m, 10H), 4.89 - 3.13 (m, 7H), 1.39 - 0.99 (m, 3H). MS
m/
z: (M+H)
+ Calc'd for C
25H
24N
7O
3: 470.19; found 470.31. HPLC retention time: 1.30 minutes (column A).
Example 112
[0587]

[0588] Example 112, was prepared from Intermediate 5f and the 2-amino-pyridin-6-yl stannane
to provide (R)-1-benzoyl-3-methyl-4-[(7-(2-amino-pyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ8.65 - 6.89 (m, 11H), 4.90 - 3.12 (m, 7H), 1.39 - 0.99 (m, 3H). MS
m/
z: (M+H)
+ Calc'd for C
26H
25N
6O
3: 469.20; found 469.32. HPLC retention time: 1.26 minutes (column A).
Example 113
[0589]

[0590] Example 113, was prepared from Intermediate 5f and the 2-amino-pyridin-5-yl stannane
to provide (R)-1-benzoyl-3-methyl-4-[(7-(2-amino-pyridin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) 88.75 - 7.19 (m, 11H), 4.91 - 3.12 (m, 7H), 1.38 -1.25 (m, 3H). MS
m/
z: (M+R)
+ Calc'd for C
26H
25N
6O
3: 469.20; found 469.34. HPLC retention time: 1.05 minutes (column A).
Example 114
[0591]

[0592] Example 114, was prepared from Intermediate 5f and the 5-amino-pyridin-2-yl stannane
to provide (R)-1-benzoyl-3-methyl-4-[(7-(5-amino-pyridin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ8.67 - 7.20 (m, 11H), 4.88 - 3.13 (m, 7H), 1.39 -1.25 (m, 3H). MS
m/
z: (M+H)
+ Calc'd for C
26H
25N
6O
3: 469.20; found 469.33. HPLC retention time: 1.22 minutes (column A).
Example 115
[0593]

Example 115, was prepared from Intermediate 5b and the 2-methylamino-pyrazin-5-yl
stannane to provide 1-benzoyl-4-[(4-methoxy-7-(2-methylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ8.90 (s, 1H), 8.61 (s, 1H), 8.18 (s, 1H), 7.92 (s, 1H), 7.46 (m, 5H), 4.12 (s,
3H), 3.85 - 3.40 (m, 8H), 3.02 (s, 3H). MS
m/
z: (M+H)
+ Calc'd for C
26H
26N
7O
4: 500.20; found 500.23. HPLC retention time: 1.24 minutes (column A).
Example 116
[0594]

[0595] Example 116, was prepared from Intermediate 5b and the 2-(2-pyrrolidinon-1-yl)-thiazol-5-yl
stannane to provide 1-benzoyl-4-[(4-methoxy-7-((2-pyrrolidinon-1-yl)-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
28H
27N
6O
5S
2: 559.18; found 559.11. HPLC retention time: 1.39 minutes (column E).
Example 117
[0596]

[0597] Example 117, was prepared from Intermediate 5b and the 2-methoxy-pyrimidin-5-yl stannane
to provide 1-benzoyl-4-[(4-methoxy-7-(2-methoxy-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
25N
6O
5: 501.19; found 501.12. HPLC retention time: 1.21 minutes (column E).
Example 118
[0598]

[0599] Example 118, was prepared from Intermediate 5b and the 2-(pyrrol-1-yl)-pyrimidin-5-yl
stannane to provide 1-benzoyl-4-[(4-methoxy-7-(2-(pyrrol-1-yl)-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
29H
26N
7O
4: 536.20; found 536.33. HPLC retention time: 1.44 minutes (column C).
Example 119
[0600]

[0601] Example 119, was prepared from Intermediate 5b and the pyrimidin-4-yl stannane to
provide 1-benzoyl-4-[(4-methoxy-7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl)]piperazine.
1H NMR (500 MHz, CD
3OD) δ9.29 (s, 1H), δ:88 (d, 1H,
J = 5.4 Hz), 8.48 (d, 1H,
J = 5.25 Hz), 8.26 (s, 1H), 8.18 (s, 1H), 7.43 (m, 5H), 4.13 (s, 3H), 3.85 - 3.47 (m,
8H). MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
6O
4: 471.18; found 471.32. HPLC retention time: 1.35 minutes (column G).
Example 120
[0602]

[0603] Example 119, was prepared from Intermediate 5b and the pyridazin-3-yl stannane to
provide 1-benzoyl-4-[(4-methoxy-7-(pyridazin-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ9.16 (s, 1H), 8.77 (d, 1H,
J = 8.5 Hz), 8.26 (d, 1H,
J = 3.05 Hz), 8.18 (s, 1H), 7.68 (m, 1H), 7.43 (m, 5H), 4.13 (s, 3H), 3.85 - 3.47 (m,
8H). MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
6O
4: 471.18; found 471.16. HPLC retention time: 1.35 minutes (column G).
Example 125
[0604]

[0605] Example 125, was prepared from Intermediate 5i and the pyrimidin-4-yl stannane to
provide 1-benzoyl-4-[(4-fluoro-7-(pyrimidin-S-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ9.36 (s, 1H), 8.96 (d, 1H,
J = 5.35 Hz), 8.58 (d, 1H,
J = 5.10 Hz), 8.43 (s, 1H), 8.38 (s, 1H), 7.43 (m, 5H), 3.85 - 3.47 (m, 8H). MS
m/
z: (M+H)
+ Calc'd for C
24H
20FN
6O
2: 459.16; found 459.15. HPLC retention time: 1.48 minutes (column A).
Example 126
[0606]

[0607] Example 126, was prepared from Intermediate 5i and the oxazol-2-yl stannane to provide
(R)-1-benzoyl-3-Methyl-4-[7-(oxazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/
z: (M+H)
+ Calc'd for C
24H
22N
5O
4: 444.17; found 444.25. HPLC retention time: 1.13 minutes (column A).
Example 131
[0608]

[0609] Example 131, was prepared from Intermediate 5p and the thiazol-2-yl stannane to provide
1-benzoyl-4-[7-(thiazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/
z: (M+H)
+ Calc'd for C
23H
20N
5O
3S: 446.13; found 446.04. HPLC retention time: 1.12 minutes (column A).
EXAMPLE 80
[0610]

[0611] Preparation of
Example 80, 1-benzoyl-4-[(4-methoxy-7-(2-amino-thioazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:
A mixture of
Example 78 (9 mg), TFA (3 mL) and water (1 mL) was stirred at 80 °C for 10 hours. After solvent
was removed under vaccum, the residue was purified by using silica gel chromatography
to afford 1-benzoyl-4-[(4-methoxy-7-(2-amino-thioazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
(3 mg); MS
m/
z: (M+H)
+ Calc'd for C
24H
23N
6O
5S: 491.15; found 491.21. HPLC retention time: 1.20 minutes (column A).
EXAMPLE 81
[0612]

[0613] Example 81, ways prepared from Intermediate 5b and the furan-3-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(furan-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
4O
5: 459.17; found 459.24. HPLC retention time: 1.13 minutes (column A).
Example 150
[0614]

[0615] Example 150, was prepared from Intermediate 5f and the 5-amino-pyrazin-2-yl stannane
to provide (R)-1-benzoyl-3-methyl-4-[(7-(5-amino-pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
24N
7O
3: 470.19; found 470.19. HPLC retention time: 1.14 minutes (column G).
Example 153
[0616]

[0617] Example 153, was prepared from Intermediate 5f and the 2-amino-pyrimidin-5-yl stannane
to provide (R)-1-benzoyl-3-methyl-4-[(7-(2-amino-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
24N
7O
3: 470.19; found 470.22. HPLC retention time: 1.07 minutes (column G).
Example 147
[0618]

[0619] Intermediate 5i (16.5 mg, 0.05 mmol) in DMF (1 mL) was treated with
N-benzoylpiperazine hydrochloride, DEBPT (15 mg, 0.05 mmol) and Hunig's base (34 µL,
0.2 mmol) at rt for 18h. The solvent was removed in vacuum and the residue was purified
by reverse phase preparative HPLC. The fractions showing the right LC/MS(ES
+) m/z (M+H)
+ = 501 were collected, concentrated and purified again using a preparative TLC (5%
MeOH/CH
2Cl
2) to afford the title compound as a white solid.
1H-NMR (500 MHz, CDCl
3) δ 11.2 (s, 1H), 10.0 (s, 1H), 9.21 (s, 1 H), 8.51 (s, 1H), 8.41 (s, 1H), 8.40 (m,
1H), 8.32 (s, 1H), 7.62 (m, 1H), 7.45 (m, soh), 3.90-3.50 (bm, 8H).
Example 156
[0620]

[0621] Example 156, was prepared from Intermediate 5b and the 4,4-dimethyloxazolin-2-yl
stannane to provide 1-benzoyl-4-[(7-(4,4-dimethyloxazolin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
27H
28N
5O
5: 490.21; found 490.22. HPLC retention time: 1.20 minutes (column C).
Example 169
[0622]

[0623] Example 169, was prepared from Intermediate 5b and the 2-(4-pyridinecarboxamido)-thiazol-5-yl
stannane to provide 1-benzoyl-4-[(7-(2-(4-pyridinecarboxanudo)-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS m/z: (M+H)
+ Calc'd for C
30H
26N
7O
5S: 596.17; found 596.14. HPLC retention time: 1.32 minutes (column C).
EXAMPLES 82-86, 98, 107, 108, 129, 130, 132, 133, 134
[0624] Examples 82-86, 98, 107,108, 127, 128, 129, 130, 132, 133 and 134 were prepared according
to the general procedure as previously described for Examples 2-14.
EXAMPLE 82
[0625]

[0626] Example 82, was prepared from Intermediate 5b and thien-2-yl boronic acid to provide
1-benzoyt-4-[(4-methoxy-7-(thiophen-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
4O
4S: 475.14; found 475.31. HPLC retention time: 1.14 minutes (column A).
EXAMPLE 83
[0627]

[0628] Example 83, was prepared from Intermediate 5b and thien-2-yl boronic acid to provide
1-benzoyl-4-[(4-methoxy-7-(thiophen-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
4O
4S: 475.14; found 475.33. HPLC retention time: 1.16 minutes (column A).
EXAMPLE 84
[0629]

[0630] Example 84, was prepared from Intermediate 5b and 5-carbonylthien-2-yl boronic acid
to provide 1-benzoyl-4-[(4-methoxy-7-(5-carbonyl-thiophen-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
23N
4O
5S: 503.14; found 503.23. HPLC retention time: 1.31 minutes (column A).
EXAMPLE 85
[0631]

[0632] Example 76, was prepared from Intermediate 5b and 5-carbonylfuran-2-yl boronic acid
to provide 1-(benzoyl)-4-[(4-methoxy-7-(5-carbonyl-furan-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
23N
4O
6: 487.16; found 487.28. HPLC retention time: 1.44 minutes (column A).
EXAMPLE 86
[0633]

[0634] Example 86, was prepared from Intermediate 5d and 4-methylthien-2-yl boronic acid
to provide 1-benzoyl-3-(R)-methyl-4-[(7-(4-methyl-thiophen-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
6H
25N
4O
3S: 473.16; found 473.26. HPLC retention time: 1.28 minutes (column A).
Example 98
[0635]

[0636] Example 98, was prepared from Intermediate 5d and 2-benzofuranyl boronic acid to
provide 1-benzoyl-3-(R)-methyl-4-[(7-(benzofuran-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CDCl
3) δ 8.24 (s, 1H), 8.09 (s, 1H), 7.70-7.26 (m, 10H), 4.03 (s, 3H), 3.97 - 3.49 (m,
8H). MS
m/
z: (M+H)
+ Calc'd for C
29H
25N
4O
5: 509.18; found 509.18. HPLC retention time: 1.50 minutes (column A).
Example 107
[0637]

[0638] Example 107, was prepared from Intermediate 5m and 2-benzofuranyl boronic acid to
provide (R)-1-picolinoyl-3-methyl-4-[(7-(benzofuran-2-yl)-6-azaindol-3 -yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ8.77 - 7.38 (m, 12H), 4.99 - 3.16 (m, 7H), 1.44 -1.27 (m, 3H). MS
m/
z: (M+H)
+ Calc'd for C
28H
24N
5O
4: 494.18; found 494.24. HPLC retention time: 1.35 minutes (column A).
Example 108
[0639]

[0640] Example 108, was prepared from Intermediate 5n and 2-benzofuranyl boronic acid to
provide (S)-1-picolinoyl-3-methyl-4-[(7-(benzofuran-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
28H
24N
5O
4: 494.18; found 494.23. HPLC retention time: 1.37 minutes (column A).
Example 127
[0641]

[0642] Example 127, was prepared from Intermediate 5i and the benzothiophen-2-yl boronic
acid to provide (R)-1-benzoyl-3-Methyl-4-U-(benzothiophen-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
29H
25N
4O
3S: 509.16; found 509.21. HPLC retention time: 1.42 minutes (column A).
Example 128
[0643]

[0644] Example 128, was prepared from Intermediate 5i and the thiophen-2-yl boronic acid
to provide (R)-1-benzoyl-3-Methyl-4-[7-(thiophen-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
4O
3S: 459.15; found 459.27. HPLC retention time: 1.22 minutes (column A).
Example 129
[0645]

[0646] Example 129, was prepared from Intermediate 5i and the thiophen-3-yl boronic acid
to provide (R)-1-benzoyl-3-Methyl-4-[7-(thiophen-3-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
4O
3S: 459.15; found 459.34. HPLC retention time: 1.31 minutes (column A).
Example 130
[0647]

[0648] Example 130, was prepared from Intermediate 5i and the 2,5-dimethyl-isoxazol-4-yl
boronic acid to provide (R)-1-benzoyl-3-Methyl-4-[7-(2,5-dimethyl-isoxazol-4-yl)-4-azainciol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
26N
5O
4: 472.20; found 472.28. HPLC retention time: 1.14 minutes (column A).
Example 132
[0649]

[0650] Example 132, was prepared from Intermediate 5p and the 2-methylcarbonyl-thiophen-5-yl
boronic acid to provide 1-benzoyl-4-[7-(2-methylcarbonyl-thiophen-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
23N
4O
4S: 487.14; found 487.20. HPLC retention time: 1.14 minutes (column A).
Example 133
[0651]

[0652] Example 133, was prepared from Intermediate 5p and the 2-carbonyl-thiophen-5-yl boronic
acid to provide 1-benzoyl-4-[7-(2-carbonyl-thiophen-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
21N
4O
4S: 473.13; found 473.11. HPLC retention time: 1.14 minutes (column A).
Example 134
[0653]

[0654] Example 134, was prepared from Intermediate 5p and the 4-methyl-thiophen-2-yl boronic
acid to provide 1-benzoyl-4-[7-(4-methyl-thiophen-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
4O
3S: 459.15; found 459.08. HPLC retention time: 1.26 minutes (column G).
Example 152
[0655]

Preparation of Example 152:
[0656] To a mixture of acid
intermediate 16 (30 mg, 68 µmol), 3-aminopyridine (26 mg, 0.27 mmol) and DMAP (50 mg, 0.41 mmol)
was added THF (2 ml), and then EDC (60 mg, 0.31 mmol). The reaction mixture was stirred
at ambient temperature for 16 hours. The LC/MS analysis indicated that the major product
was the activated ester. The reaction mixture was then added into a DMF (2 ml) solution
of 3-aminopyridine (400 mg, 4.25 mmol) and stirred at ambient temperature for 16 hours.
After addition of MeOH (4 ml), the reaction mixture was purified by preparative reverse
phase HPLC to give the TFA salt of the title compound using the method: Start %B =
30, Final %B = 75, Gradient time = 25 min, Flow Rate = 25 ml/min, Column : YMC C18
5um 20 x 100mm, Fraction Collection: 10.41 - 11.08 min.
1H NMR: (DMSO-
d6) δ 13.04 (s, 1H), 11.17 (s, 1H), 9.17 (s, 1H), 8.53 (s, 1H), 8.35 (m, 3H), 7.44 (b
s, 6H), 3.75 - 3.37 (b m, 8H);
LC/MS: (ES+) m/z (M+H)
+ = 517, 519; HPLC R
t = 1.653.
Example 143
[0657]

Prep of Example 143:
[0658] To a mixture of intermediate 5q (31 mg, 65 µmol) and Pd(PPh
3)
4 (20 mg, 17 µmol) was added 1,4-dioxane (1 ml) and ii (30 mg, 78 µmol). The reaction
mixture was heated in a sealed tube at 145°C for 4 hours. After cooling to ambient
temperature, the reaction mixture was added MeOH (4 ml) and then filtered. The filtrate
was purified by preparative reverse phase HPLC to give the TFA salt of the title compound
using the method: Start %B = 25, Final %B = 90, Gradient time = 20 min, Flow Rate
= 25 ml/min, Column : YMC C18 5um 20 x 100mm, Fraction Collection: 11.14 - 11.92 min.
1H NMR: (DMSO-
d6) δ 12.71 (s, 1H), 9.01 (s, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.44 (b
s, 5H), 7.44 (b s, 2H), 3.75 - 3.37 (b m, 8H);
LC/MS: (ES+) m/z (M+H)
+= 490, 492; HPLC R
t = 2.250.
Example 149
[0659]

Preparation of Example 49:
[0660] To a suspension of compound of Example 143 (12 mg, 24 µmol) in sulfuric acid (5%,
2 ml), was charged sodium nitrite (22 mg, 0.32 mol) at 0°C. The reaction mixture was
stirred at 0°C for 30 minutes and then at ambient temperature for 1 hour. After addition
of MeOH (4 ml), the reaction mixture was purified by preparative reverse phase HPLC
to give a TEA solvate of title compound using the method: Start %B = 20, Final %B
= 85, Gradient time = 15 min, Flow Rate = 25 ml/min, Column : YMC C18 5um 20 x 100mm,
Fraction Collection: 10.67- 11.36 min.
1H NMR: (DMSO-
d6) δ 12.62 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.44 (b
s, 5H), 3.80 - 3.30 (b m, 8H);
LC/MS: (ES+) m/z (M+H)
+ = 491, 493; HPLC R
t = 2.193.
Example 144
[0661]

Preparation of Example 144:
[0662] To a mixture of intermediate 5q (50 mg, 105 µmol) and Pd(PPh
3)
4 (50 mg, 43 µmol) was added 1,4-dioxane (1 ml) and iii (77 mg, 210 µmol). The reaction
mixture was heated in a sealed tube at 145°C for 16 hours. After cooling to ambient
temperature, the reaction mixture was added MeOH (4 ml) and then filtered. The filtrate
was purified by reverse phase HPLC to give the TFA salt of the title compound of using
the method: Start %B = 15, Final %B = 100, Gradient time = 20 min, Flow Rate = 25
ml/min, Column : YMC C18 5um 20 x 100mm, Fraction Collection: 11.80 - 12.31 min.
1H NMR: (CD
3OD) δ 9.32 (s, 1H), 9.25 (s, 2H), 8.50 (s, 1H), 8.44 (s, 1H), 7.47 (b s, 5H), 4.00
- 3.44 (b m, 8H);
LC/MS: (ES+) m/z (M+H)
+ = 475, 477; HPLC R
t = 1.833.
EXAMPLE 87
[0663]

[0664] Preparation of
Example 87, 1-benzoyl-4-[(4-methoxy-7-(2-hydroxycarbonyl-furan-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:
A mixture of the compound of
Example 85 (19 mg), NaClO
2 (9.2 mg) in a mixed solution of CH
3CN (3 mL) and water (0.5 mL) was stirred at room temperature for 24 hours. After the
reaction was quenched by 1N NaOH solution (1 ml), the mixture was extracted with diethyl
ether (3 x 10 mL). The aqueous phase was acidified with 1N HCl to give a yellow solid
precipitate (5mg) which was the product shown. MS
m/
z: (M+H)
+ Calc'd for C
26H
23N
6O
7: 503.16; found 503.19. HPLC retention time: 1.37 minutes (column A).
General Procedure of Converting -NH2 Group to -NHCOR Group
[0665] Preparation of Example 99, 1-(benzoyl)-4-[(4-methoxy-7-(2-acetylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:
1-(benzoyl)-4-[(4-methoxy-7-(2-amino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
(4mg) andacetic anhydride (20mg) were dissolved in pyridine (0.5ml). The reaction
was stirred for three hours at room temperature. After reaction was quenched with
Meoh (1ml), solvents were concentrated to give a residue which was purified using
a Shimadzu automated preparative HPLC System to provide 3.0 mg of the desired compound,
1-(benzoyl)-4-[(4-methoxy-7-(2-acetylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ9.58 (s, 1H), 9.25 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 7.49 (m, 5H), 4.12 (s,
3H), 3.84 - 3.35 (m, 8H), 2.27 (s, 3H). MS
m/
z: (M+H)
+ Calc'd for C
27H
26N
7O
5: 528.20; found 528.22. HPLC retention time: 1.33 minutes (column A).
General Procedure of Converting -NH2 Group to -OH Group
[0666] Preparation of Example 97, 1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:
1-(benzoyl)-4-[(4-methoxy-7-(2-amino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
(15 mg) and NaNO
2 (10 mg) was added into a H
2SO
4 solution (0.1ml of concentrated H
2SO
4 diluted with 0.3 ml of water). The reaction was stirred at room temperature for one
hour. Then, the reaction mixture was neutralized with a saturated Na
2CO
3 solution (10 ml). The solvents were concentrated to give a residue which was purified
using a Shimadzu automated preparative HPLC System to provide 4.2mg of the desired
compound, 1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
1H NMR (500 MHz, CD
3OD) δ8.55 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.49 (m, 5H), 4.12 (s,
3H), 3.84 - 3.64 (m, 8H). MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
6O
5: 487.17; found 487.22. HPLC retention time: 1.13 minutes (column A).

This general procedure is applied to prepare examples 121, 122,123,124,155, 157, and
162.
Example 121
[0667]

[0668] Example 121, (R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
6O
4: 471.18; found 471.17. HPLC retention time: 1.39 minutes (column G).
Example 121-2
[0669]

[0670] Example 121-2, (R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-4-oxo-pyrazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
was isolated during the preparation of Example 121. MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
6O
5: 487.17; found 487.17. HPLC retention time: 1.08 minutes (column G).
Example 122
[0671]

[0672] Example 122, (R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-pyridin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
24N
5O
4: 470.18; found 470.17. HPLC retention time: 1.03 minutes (column G).
Example 123
[0673]

[0674] Example 123, (R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-pyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
24N
5O
4: 470.18; found 470.14. HPLC retention time: 1.28 minutes (column G).
Example 124
[0675]

[0676] Example 124, (R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(5-hydroxyl-pyridin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
24N
5O
4: 470.18; found 470.13. HPLC retention time: 1.21 minutes (column G).

Preparation of Example 138
[0677]

[0678] Preparation of Example 138, 1-(benzoyl)-4-[(4-methoxy-7-(1-methylpyrazin-2-on-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:
1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
(6mg), MeI (5mg) and K
2CO
3 (4 mg)were dissolved in acetone (5 ml). The reaction was stirred for four hours at
room temperature. After solid was filtered away, the mother liquid was concentrated
to give a residue which was purified using a Shimadzu automated preparative HPLC System
to provide 3.0 mg of the desired compound, 1-(benzoyl)-4-[(4-methoxy-7-(1-methylpyrazin-2-on-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
25N
6O
5: 501.19; found 501.14. HPLC retention time: 1.08 minutes (column G).
Example 139
[0679]

[0680] Intermediate 4i was dissolved in DMF (2 ml), and to which
N-benzoyl-(
R)-methylpiperazine hydrochloride (0.092 g, 0.45 mmol) and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3
H)-one (DEPBT, 0.180 g, 0.60 mmol) were added, followed by
N,N-diisopropylethylamine (0.15 ml, 0.87 mmol). The reaction mixture was stirred for
2 h at r.t., and then the volatile evaporated under high vacuum. Water was added to
the mixture to induce precipitation, and the solids were filtered and dried
in vacuo. Purification of the crude solid by preparative thin layer chromatography (5% MeOH/
CH
2Cl
2), and subsequent washing with ether gave
the title compound; 1H NMR: (CDCl
3) δ 8.78 (s, 1H), 8.32 (s, 1H), 8.28 (s, 1H) 7.84 (s, 1H), 7.44 (b s, 5H), 6.56 (s,
1H), 5.00-3.00 (b m, 7H), 1.45-1.20 (b s, 3H);
LC/MS: (ES+) m/z (M+H)
+ = 521, 523; HPLC R
t = 1.677
Example 140
[0681]

[0682] The title compound was prepared according to general procedures described before
(Sn-coupling). H NMR: 8.41(m, 1H); 8.33(m, 1H); 8.16(m, 1H); 7.53(m, 1H); 7.47(bs,
5H); 3.97-3.54(m, 8H). LC/MS: (ES
+) m/z(m+H)
+ = 448, Rt = 1.28min.
Example 141
[0683]

[0684] The title compound was prepared according to general procedures described before
(Sn-coupling).
1H-NMR: 9.71-9.70(m, 1H); 8.80-8.79(m, 1H); 8.66-8.42(m, 2H); 8.41-8.35(m, 2H); 7.99-7.92(m,1H),
7.69-7.53(m, 1H); 7.48-7.44(m, 1H); 5.05-3.15(m, 8H). LC/MS: (ES
+) m/z (m+H)
+ = 474. Rt = 1.26min.
Example 144
[0685]

Preparation of Example 144:
[0686] To a mixture of intermediate 5q (50 mg, 105 µmol) and Pd(PPh
3)
4 (50 mg, 43 µmol) was added 1,4-dioxane (1 ml) and iii (77 mg, 210 µmol). The reaction
mixture was heated in a sealed tube at 145°C for 16 hours. After cooling to ambient
temperature, the reaction mixture was added MeOH (4 ml) and then filtered. The filtrate
was purified by reverse phase HPLC to give the TFA salt of the title compound of using
the method: Start %B = 15, Final %B =100, Gradient time = 20 min, Flow Rate = 25 ml/min,
Column : YMC C18 5um 20 x 100mm, Fraction Collection: 11.80 - 12.31 min.
1H NMR: (CD
3OD) δ 9.32 (s, 1H), 9.25 (s, 2H), 8.50 (s, 1H), 8.44 (s, 1H), 7.47 (b s, 5H), 4.00
- 3.44 (b m, 8H);
LC/MS: (ES+) m/z (M+H)
+ = 475, 477; HPLC R
t = 1.833.
Example 145
[0687]

[0688] The title compound was prepared following the procedure described before for example
146 and intermediate 4k.
1H NMR: 8.35-8.33(m, 2H); 8.11(s, 1H); 7.89(s, 1H); 7.43(bs, 5H); 3.89-3.49(m, 8H).
LC/MS: (ES
+) m/z (M+H)
+ = 448. Rt = 1.18min.
Example 146
[0689]

[0690] Intermediate 4m (0.26 mmol) was dissolved in DMF (1 mL) and treated with
N-benzoylpiperazine hydrochloride (59 mg, 0.26 mmol), DEBPT (79 mg, 0.26 mmol) and Hunig's
base (90 µL, 0.52 mmol) and the reaction mixture was stirred at rt for 18h. The solvent
was removed in vacuum and the residue was purified by reverse phase preparative HPLC.
The fractions showing the right LC/MS:(ES
+) m/z (M+H)
+ = 449 were collected, concentrated and purified again using a preparative TLC (5%
MeOH/CH
2Cl
2) to afford the title compound as a white solid.
1H-NMR (500 MHz, CDCl
3) δ 10.7 (s, 1H), 9.00 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 7.45 (m, 5H), 3.9-3.5
(bm, 8H).
Example 148
[0691]

[0692] The title compound was prepared from intermediate 4n using the same coupling conditions
described for the last step of the preparation of intermediate 5i.
1H NMR: 8.82(m, 1H); 8.48-8.45(m, 1H); 8.37-8.33(m, 1H); 8.26-8.23(m, 1H); 7.47(bs,
5H); 3.97-3.54(m, 8H). LC/MS: (ES
+ m/z(m+H)
+ = 447 Rt = 0.94min.
Example 151
[0693]

[0694] Example 151, was prepared from Intermediate 51 and the thiazol-5-yl stannane to provide
1-picolinoyl-4-[(4-methoxy-7-(thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
23H
21N
6O
4S: 477.13; found 477.13. HPLC retention time: 0.94 minutes (column G).
Example 154
[0695]

[0696] The title compound was prepared according to general procedures described before
(Sn-coupling).
1H-NMR: 9.23-9.22 (m, 1H); 8.83-8.81(m, 1H); 8.43 (m, 1H); 8.36 (m, 1H); 7.75-7.73
(m,1H), 7.44 (bs, 5H); 3.85-3.49 (m, 8H). LC/MS: (ES
+) m/z (M+H)
+ = 459. Rt = 1.39min.
Example 155
[0697]

[0698] Example 155, 1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
6O
5: 487.17; found 487.14. HPLC retention time: 1.30 minutes (column G).
Example 157
[0699]

[0700] Example 157, (R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(5-hydroxyl-pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
6O
4: 471.18; found 471.16. HPLC retention time: 1.09 minutes (column G).
Example 161
[0701]

[0702] Procedure as usual to yield A: 1H NMR (500 MHz, DMSO) δ 9.67 (s, 1H), 8.81 (s, 1H), 8.72 (d,
J = 5.4 Hz, 1H), 8.25 (d,
J = 6.1 Hz, 1H), 8.00 (dd,
J = 8.2, 1.8 Hz, 1H), 7.68 (dd,
J= 8.2, 7.4 Hz, 2H), 7.60 (tt,
J= 7.4, 1.8 Hz, 2H), 7.48 (br s, 5H), 4.04-3.46 (m, 8H). MS
m/
z: (M+H)
+ calcd for C
28H
24N
7O
3: 506.19; found 506.15. HPLC retention time: 1.21 minutes (XTERRA C18 S7 3.0 x 50
mm)).
Example 162
[0703]

[0704] Example 162, (R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
25H
23N
6O
4: 471.18; found 471.13. HPLC retention time: 0.95 minutes (column G).
Example 163
[0705]

[0706] To a solution of intermediate 5q (50 mg, 0.11 mmol) in DMF (1 ml) was added CuCN
(30 mg, 0.335 mmol). The reaction mixture was heated at 170°C for 30 min. After cooling
to ambient temperature, the reaction mixture was diluted with MeOH (15 ml), filtered
under gravity, and the filtrate evaporated
in vacuo to afforded a brownish residue which is a cyanointermediate. To the residue in DMF
(1 ml) was added sodium azide (61 mg, 0.95 mmol) and ammonium chloride (50 mg, 0.95
mmol). The mixture was heated at 90°C for one hour. The reaction mixture was then
diluted with MeOH (4 ml), filtered, and the filtrate purified by preparative reverse
phase HPLC using the method: Start %B = 20, Final %B = 80, Gradient time = 15 min,
Flow Rate = 40 ml/min, Column : XTERRA C18 5 um 30 x 100 mm, Fraction Collection:
11.26 - 11.71 min. The material was homogenous by
1H NMR and HPLC, although the mass spectrum indicated an extra peak at (M+H)
+ = 431;
1H NMR: (CD
3OD) 8.41 (s, 1H), 8.12 (s, 1H), 7.47 (b s, 5H), 3.97 - 3.47 (b m, 8H);
LC/MS: (ES+) m/z (M+H)
+= 465, 467; HPLC R
t = 1.937
Example 164
[0707]

[0708] Example 164, was prepared from Intermediate 5a and the 4-hydroxycarbonylphenyl boronic
acid to provide 1-benzoyl-4-[7-(4-hydroxycarbonylphenyl)-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
28H
25N
4O
5: 497.18; found 497.22. HPLC retention time: 1.20 minutes (column C).
Example 165
[0709]

[0710] Compound of Example
165 was prepared in a similar manner to compound of Example
143 starting with intermediate
5r, but at 125°C for 22 hours and purification by preparative thin layer chromatography
(4% MeOH/CH
2Cl
2).
1H NMR: (CDCl
3) δ 11.85 (s, 1H), 9.91 (d,
J= 1.6 Hz, 1H), 8.70 (d,
J= 2.6 Hz, 1H), 8.65 (dd,
J = 1.6, 2.6 Hz, 1H), 8.52 (s, 1H), 8.35 (d,
J = 3.1 Hz, 1H), 3.73 (b m, 2H), 3.56 (b m, 4H), 3.53 (b m, 2H), 1.48 (s, 9H);
LC/MS: (ES+) m/z (M+H)
+= 471, 473; HPLC R
t = 1.690.
Example 167
[0711]

[0712] Intermediate 4m (0.098 mmol) was dissolved in DMF (1 mL) and treated with
N-[5-(2-Bromofuroyl)]piperazine hydrochloride (30 mg, 0.098 mmol), DEBPT (60 mg, 0.19
mmol) and Hunig's base (70 µL, 0.19 mmol) and the reaction mixture was stirred at
rt for 18h. The solvent was removed in vacuum and the residue was purified by reverse
phase preparative HPLC. The fractions showing the right LC/MS:(ES
+) m/z (M+H)
+ = 518,520 were collected, concentrated and purified again using a preparative TLC
(5% MeOH/CH
2Cl
2) to afford the title compound as a white solid.
1H-NMR (500 MHz, CDCl
3) δ 10.7 (s, 1H), 9.00 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 7.06 (d,
J=3.4 Hz, 1H), 6.46 06 (d,
J=3.4 Hz, 1H), 3.90-3.66 (bm, 8H).
Example 168
[0713]

[0714] Example 168, 1-benzoyl-3-(R)-methyl-4-[(7-(2-thienylcarbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine,
was prepared from a reaction 1-benzoyl-3-(R)-methyl-4-[(7-(methoxymethylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine
and 2-thienyl lithium by using the same procedure for the preapartion of I-64, 1-benzoyl-3-(R)-methyl-4-[(7-(2-propynyl)carbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS
m/
z: (M+H)
+ Calc'd for C
26H
23N
4O
4S: 487.14; found 487.11. HPLC retention time: 1.31 minutes (column A).
6 and hereafter, the following definitions apply.
Biology
[0715]
- "µM" means micromolar;
- "mL" means milliliter;
- "µl" means microliter;
- "mg" means milligram;
[0716] The materials and experimental procedures used to obtain the results reported in
Tables 1-5 are described below.
Cells:
[0717]
- Virus production-Human embryonic Kidney cell line, 293, propagated in Dulbecco's Modified Eagle Medium (Life
Technologies, Gaithersburg, MD) containing 10% fetal Bovine serum (FBS, Sigma, St.
Louis, MO).
- Virus infection- Human epithelial cell line, HeLa, expressing the HIV-1 receptors CD4 and CCR5 was
propagated in Dulbecco's Modified Eagle Medium (Life Technologies, Gaithersburg, MD)
containing 10% fetal Bovine serum (FBS, Sigma, St. Louis , MO) and supplemented with
0.2 mg/mL Geneticin (Life Technologies, Gaithersburg, MD) and 0.4 mg/mL Zeocin (Invitrogen,
Carlsbad, CA).
[0718] Virus-Single-round infectious reporter virus was produced by co-transfecting human embryonic
Kidney 293 cells with an HIV-1 envelope DNA expression vector and a proviral cDNA
containing an envelope deletion mutation and the luciferase reporter gene inserted
in place of HIV-1 nef sequences (Chen et al, Ref. 41). Transfections were performed
using lipofectAMINE PLUS reagent as described by the manufacturer (Life Technologies,
Gaithersburg, MD).
Experiment
[0719]
- 1. Compound was added to HeLa CD4 CCR5 cells plated in 96 well plates at a cell density
of 5 X 104 cells per well in 100 µl Dulbecco's Modified Eagle Medium containing 10 % fetal Bovine
serum at a concentration of <20 µM.
- 2. 100 µl of single-round infectious reporter virus in Dulbecco's Modified Eagle Medium
was then added to the plated cells and compound at an approximate multiplicity of
infection (MOI) of 0.01, resulting in a final volume of 200 µl per well and a final
compound concentration of <10 µM.
- 3. Samples were harvested 72 h after infection.
- 4. Viral infection was monitored by measuring luciferase expression from viral DNA
in the infected cells using a luciferase reporter gene assay kit (Roche Molecular
Biochemicals, Indianapolis, IN). Infected cell supernatants were removed and 50 µl
of Dulbecco's Modified Eagle Medium (without phenol red) and 50 µl of luciferase assay
reagent reconstituted as described by the manufacturer (Roche Molecular Biochemicals,
Indianapolis, IN) was added per well. Luciferase activity was then quantified by measuring
luminescence using a Wallac microbeta scintillation counter.
- 5. The percent inhibition for each compound was calculated by quantifying the level
of luciferase expression in cells infected in the presence of each compound as a percentage
of that observed for cells infected in the absence of compound and subtracting such
a determined value from 100.
- 6. An EC50 provides a method for comparing the antiviral potency of the compounds of this invention.
The effective concentration for fifty percent inhibition (EC50) was calculated with the Microsoft Excel Xlfit curve fitting software. For each compound,
curves were generated from percent inhibition calculated at 10 different concentrations
by using a four paramenter logistic model (model 205). The EC50 data for the compounds is shown in Tables 5-6. Table 1 is the key for the data in
Tables 5-6.
Results
[0720]
Table 4. Biological Data Key for EC
50s
Compounds* with EC50a >5µM |
Compounds with EC50a >1 µM but <5µM |
Compounds with EC50 >50nM but not yet tested at higher concentrations |
Compounds with EC50 < 1 µM |
Group C |
Group B |
Group A' |
Group A |
*Some of these compounds may have been tested at a concentration lower than their
EC50 but showed some ability to cause inhibition and thus should be evaluated at a higher
concentration to determine the exact EC50. |
[0722] The 5-aza inhibitors shown in Table 8 can be prepared from intermediates 1a or 2s
or the corresponding 7-desbromo-7-chloro intermediates which are prepared analogously
and the methods herein or by using other methods described herein.
[0725] The compounds of Table 11 below were all found to be very potent in the assay described
above using % inhibition as a criteria. In Table 11, X
2, X
4 etc. indicates the point of attachment. The vast majority of the compounds exhibited
greater than 98% inhibition at a concentration of 10uM. The data at 10µM was calculated
in the following manner:
Method for extrapolating % inhibition at 10µM
[0726] The compounds of Table 11 below were all found to be very potent in the assay described
above using % inhibition as a criteria. In Table 8 X
2, X
4 etc. indicates the point of attachment. The vast majority of the compounds exhibited
greater than 98% inhibition at a concentration of 10µM. The data at 10µM was calculated
in the following manner:
Method for extrapolating % inhibition at 10µM
[0727] The data in Table 11 was obtained using the general procedures above and by the following
methods. Data is not reported for all compounds since data for all the compounds is
reported by the alternate method in Table 5. The percent inhibition for each compound
was calculated by quantifying the level of luciferase expression in cells infected
in the presence of compound as a percentage of that observed for cells infected in
the absence of compound and subtracting such a determined value from 100. For compounds
tested at concentrations less than 10 µM, the percent inhibition at 10 µM was determined
by extrapolation using the XLfit curve fitting feature of the Microsoft Excel spreadsheet
software. Curves were obtained from 10 data points (% inhibition determined at 10
concentrations of compound) by using a four parameter logistic model (XLfit model
205: y = A + ((B-A)/(1+((C/x)
D)), where, A = minimum y, B = maximum y, C = logEC
50, D = slope factor, and x and y are known data values. Extrapolations were performed
with the A and B parameters unlocked.
[0728] Thus the compounds of this invention are all potent antiviral inhibitors based on
this assay.
Table 11
Compound # |
Average % inhibition at 10 µM |
|
|
Intermediate 8 |
85% |
Example 1 |
56% |
|
|
[0729] The compounds of the present invention may be administered orally, parenterally (including
subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion
techniques), by inhalation spray, or rectally, in dosage unit formulations containing
conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
[0730] Thus, in accordance with the present invention there is further provided a method
of treating and a pharmaceutical composition for treating viral infections such as
HIV infection and AIDS. The treatment involves administering to a patient in need
of such treatment a pharmaceutical composition comprising a Pharmaceutical carrier
and a therapeutically-effective amount of a compound of the present invention.
[0731] The pharmaceutical composition may be in the form of orally-administrable suspensions
or tablets; nasal sprays, sterile injectable preparations, for example, as sterile
injectable aqueous or oleagenous suspensions or suppositories.
[0732] When administered orally as a suspension, these compositions are prepared according
to techniques well-known in the art of pharmaceutical formulation and may contain
microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as
a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring
agents known in the art. As immediate release tablets, these compositions may contain
microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose
and/or other excipients, binders, extenders, disintegrants, diluents and lubricants
known in the art.
[0733] The injectable solutions or suspensions may be formulated according to known art,
using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol,
1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or
suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed
oils, including synthetic mono- or diglycerides, and fatty acids, including oleic
acid.
[0734] The compounds of this invention can be administered orally to humans in a dosage
range of 1 to 100 mg/kg body weight in divided doses. One preferred dosage range is
1 to 10 mg/kg body weight orally in divided doses. Another preferred dosage range
is 1 to 20 mg/kg body weight orally in divided doses. It will be understood, however,
that the specific dose level and frequency of dosage for any particular patient may
be varied and will depend upon a variety of factors including the activity of the
specific compound employed, the metabolic stability and length of action of that compound,
the age, body weight, general health, sex, diet, mode and time of administration,
rate of excretion, drug combination, the severity of the particular condition, and
the host undergoing therapy.
[0735] Scheme 41a depicts methodology for converting a carboxylic acid to an alkynyl ketone.
The alkynyl ketone intermediates can then be converted to pyrazoles or isoxazoles
upon reaction with hydrazines or hydroxyl amines, respectively.